Cytokine inhibitors

ABSTRACT

Disclosed are compounds of formula (I)  
                 
 
     Where Ar 1 , X, Y, Q, W, R 3 , R 4 , R 5 , R 6  and R y  are defined herein. The compounds of the invention inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. The compounds are also useful for treating diseases or conditions related to oncology and anticoagulant or fibrinolytic therapy. Also disclosed are processes for preparing these compounds and pharmaceutical compositions comprising these compounds.

[0001] This application claims benefit to U.S. provisional applicationNo. 60/453,364 filed Mar. 10, 2003.

BACKGROUND OF THE INVENTION

[0002] 1. Technical Field

[0003] This invention relates to compounds of formula (I)

[0004] The compounds of the invention inhibit production of cytokinesinvolved in inflammatory processes and are thus useful for treatingdiseases and pathological conditions involving inflammation such aschronic inflammatory disease. This invention also relates to processesfor preparing these compounds and to pharmaceutical compositionscomprising these compounds.

[0005] 2. Background Information

[0006] Tumor necrosis factor (TNF) and interleukin-1 (IL-1) areimportant biological entities collectively referred to asproinflammatory cytokines which play a role in cytokine mediateddiseases. These, along with several other related molecules, mediate theinflammatory response associated with the immunological recognition ofinfectious agents. The inflammatory response plays an important role inlimiting and controlling pathogenic infections. Elevated levels ofproinflammatory cytokines are also associated with a number of diseasesof autoimmunity such as toxic shock syndrome, rheumatoid arthritis,osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C.A., et al., 1984, Rev. Infect. Disease 6:51). In these diseases, chronicelevation of inflammation exacerbates or causes much of thepathophysiology observed. For example, rheumatoid synovial tissuebecomes invaded with inflammatory cells that result in destruction tocartilage and bone (Koch, A. E., et al., 1995, J. Invest. Med. 43:28-38). Studies suggest that inflammatory changes mediated by cytokinesmay be involved in endothelial cell pathogenesis including restenosisafter percutaneous transluminal coronary angioplasty (PTCA) (Tashiro,H., etal., 2001 March, Coron Artery Dis 12(2):107-13). An important andaccepted therapeutic approach for potential drug intervention in thesediseases is the reduction of proinflammatory cytokines such as TNF (alsoreferred to in its secreted cell-free form as TNFα) and IL-1β. A numberof anti-cytokine therapies are currently in clinical trials. Efficacyhas been demonstrated with a monoclonal antibody directed against TNFαin a number of autoimmune diseases (Heath, P., “CDP571: An EngineeredHuman IgG4 Anti-TNFα Antibody” IBC Meeting on Cytokine Antagonists,Philadelphia, Pa., Apr. 24-5, 1997). These include the treatment ofrheumatoid arthritis, Crohn's disease and ulcerative colitis (Rankin, E.C. C., et al., 1997, British J. Rheum. 35: 334-342 and Stack, W. A., etal., 1997, Lancet 349: 521-524). The monoclonal antibody is thought tofunction by binding to both soluble TNFα and to membrane bound TNF.

[0007] A soluble TNFα receptor has been engineered that interacts withTNFα. The approach is similar to that described above for the monoclonalantibodies directed against TNFα; both agents bind to soluble TNFα, thusreducing its concentration. One version of this construct, called Enbrel(Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase IIIclinical trial for the treatment of rheumatoid arthritis (Brower et al.,1997, Nature Biotechnology 15: 1240). Another version of the TNFαreceptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) hasdemonstrated efficacy in various animal models of allergic lunginflammation and acute lung injury. Ro 45-2081 is a recombinant chimericmolecule constructed from the soluble 55 kDa human TNF receptor fused tothe hinge region of the heavy chain IgG1 gene and expressed ineukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143). IL-1has been implicated as an immunological effector molecule in a largenumber of disease processes. IL-1 receptor antagonist (IL-1ra) had beenexamined in human clinical trials. Efficacy has been demonstrated forthe treatment of rheumatoid arthritis (Antril, Amgen). In a phase IIIhuman clinical trial IL-1ra reduced the mortality rate in patients withseptic shock syndrome (Dinarello, 1995, Nutrution 11, 492).Osteoarthritis is a slow progressive disease characterized bydestruction of the articular cartilage. IL-1 is detected in synovialfluid and in the cartilage matrix of osteoarthritic joints. Antagonistsof IL-1 have been shown to diminish the degradation of cartilage matrixcomponents in a variety of experimental models of arthritis (Chevalier,1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator ofcardiovascular homeostasis, neurotransmission and immune function;recently it has been shown to have important effects in the modulationof bone remodeling. Cytokines such as IL-1 and TNF are potentstimulators of NO production. NO is an important regulatory molecule inbone with effects on cells of the osteoblast and osteoclast lineage(Evans, et al., 1996, J Bone Miner Res. 11, 300). The promotion ofbeta-cell destruction leading to insulin dependent diabetes mellitusshows dependence on IL-1. Some of this damage may be mediated throughother effectors such as prostaglandins and thromboxanes. IL-1 can effectthis process by controlling the level of both cyclooxygenase II andinducible nitric oxide synthetase expression (McDaniel et al., 1996,Proc Soc Exp Biol Med. 211, 24).

[0008] Inhibitors of cytokine production are expected to block induciblecyclooxygenase (COX-2) expression. COX-2 expression has been shown to beincreased by cytokines and it is believed to be the isoform ofcyclooxygenase responsible for inflammation (M. K. O'Banion et al.,Proc. Natl. Acad. Sci. U.S.A, 1992, 89,4888.) Accordingly, inhibitors ofcytokines such as IL-1 would be expected to exhibit efficacy againstthose disorders currently treated with COX inhibitors such as thefamiliar NSAIDs. These disorders include acute and chronic pain as wellas symptoms of inflammation and cardiovascular disease.

[0009] Elevation of several cytokines have been demonstrated duringactive inflammatory bowel disease (IBD). A mucosal imbalance ofintestinal IL-1 and IL-1ra is present in patients with IBD. Insufficientproduction of endogenous IL-1ra may contribute to the pathogenesis ofIBD (Cominelli, et al., 1996, Aliment Pharmacol Ther. 10, 49). Alzheimerdisease is characterized by the presence of beta-amyloid proteindeposits, neurofibrillary tangles and cholinergic dysfunction throughoutthe hippocampal region. The structural and metabolic damage found inAlzheimer disease is possibly due to a sustained elevation of IL-1(Holden, et al., 1995, Med Hypotheses, 45, 559). A role for IL-1 in thepathogenesis of human immunodeficiency virus (HIV) has been identified.IL-1ra showed a clear relationship to acute inflammatory events as wellas to the different disease stages in the pathophysiology of HIVinfection (Kreuzer, et al., 1997, Clin Exp Immunol. 109, 54). IL-1 andTNF are both involved in periodontal disease. The destructive processassociated with periodontal disease may be due to a disregulation ofboth IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).

[0010] Proinflammatory cytokines such as TNFα and IL-1β are alsoimportant mediators of septic shock and associated cardiopulmonarydysfunction, acute respiratory distress syndrome (ARDS) and multipleorgan failure. In a study of patients presenting at a hospital withsepsis, a correlation was found between TNFα and IL-6 levels and septiccomplications (Terregino et al., 2000, Ann. Emerg. Med., 35, 26). TNFαhas also been implicated in cachexia and muscle degradation, associatedwith HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85, 289).Obesity is associated with an increase incidence of infection, diabetesand cardiovascular disease. Abnormalities in TNFα expression have beennoted for each of the above conditions (Loffreda, et al., 1998, FASEB J.12, 57). It has been proposed that elevated levels of TNFα are involvedin other eating related disorders such as anorexia and bulimia nervosa.Pathophysiological parallels are drawn between anorexia nervosa andcancer cachexia (Holden, et al., 1996, Med Hypotheses 47, 423). Aninhibitor of TNFα production, HU-211, was shown to improve the outcomeof closed brain injury in an experimental model (Shohami, et al., 1997,J. Neuroimmunol. 72, 169). Atherosclerosis is known to have aninflammatory component and cytokines such as IL-1 and TNF have beensuggested to promote the disease. In an animal model an IL-1 receptorantagonist was shown to inhibit fatty streak formation (Elhage et al.,1998, Circulation, 97, 242). TNFα levels are elevated in airways ofpatients with chronic obstructive pulmonary disease and it maycontribute to the pathogenesis of this disease (M. A. Higham et al.,2000, Eur. Respiratory J., 15, 281). Circulating TNFα may alsocontribute to weight loss associated with this disease (N. Takabatake etal., 2000, Amer. J. Resp. & Crit. Care Med., 161 (4 Pt 1), 1179).Elevated TNFα levels have also been found to be associated withcongestive heart failure and the level has been correlated with severityof the disease (A. M. Feldman et al., 2000, J. Amer. College ofCardiology, 35, 537). In addition, TNFα has been implicated inreperfusion injury in lung (Borjesson et al., 2000, Amer. J. Physiol.,278, L3-12), kidney (Lemay et al., 2000, Transplantation, 69, 959), andthe nervous system (Mitsui et al., 1999, Brain Res., 844, 192).

[0011] TNFα is also a potent osteoclastogenic agent and is involved inbone resorption and diseases involving bone resorption (Abu-Amer et al.,2000, J. Biol. Chem., 275, 27307). It has also been found highlyexpressed in chondrocytes of patients with traumatic arthritis(Melchiorri et al., 2000, Arthritis and Rheumatism, 41, 2165). TNFα hasalso been shown to play a key role in the development ofglomerulonephritis (Le Hir et al., 1998, Laboratory Investigation, 78,1625).

[0012] The abnormal expression of inducible nitric oxide synthetase(iNOS) has been associated with hypertension in the spontaneouslyhypertensive rat (Chou et al., 1998, Hypertension, 31, 643). IL-1 has arole in the expression of iNOS and therefore may also have a role in thepathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension,9, 867).

[0013] IL-1 has also been shown to induce uveitis in rats which could beinhibited with IL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol.and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have beenshown to stimulate proliferation of acute myelogenous leukemia blasts(Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essentialfor the development of both irritant and allergic contact dermatitis.Epicutaneous sensitization can be prevented by the administration of ananti-IL-1 monoclonal antibody before epicutaneous application of anallergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Dataobtained from IL-1 knock out mice indicates the critical involvement infever for this cytokine (Kluger et al., 1998, Clin Exp PharmacolPhysiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 andIL-8 initiate the acute-phase reaction which is stereotyped in fever,malaise, myalgia, headaches, cellular hypermetabolism and multipleendocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813).The production of these inflammatory cytokines rapidly follows trauma orpathogenic organism invasion.

[0014] Other proinflammatory cytokines have been correlated with avariety of disease states. IL-8 correlates with influx of neutrophilsinto sites of inflammation or injury. Blocking antibodies against IL-8have demonstrated a role for IL-8 in the neutrophil associated tissueinjury in acute inflammation (Harada et al., 1996, Molecular MedicineToday 2, 482). Therefore, an inhibitor of IL-8 production may be usefulin the treatment of diseases mediated predominantly by neutrophils suchas stroke and myocardial infarction, alone or following thrombolytictherapy, thermal injury, adult respiratory distress syndrome (ARDS),multiple organ injury secondary to trauma, acute glomerulonephritis,dermatoses with acute inflammatory components, acute purulent meningitisor other central nervous system disorders, hemodialysis, leukopherisis,granulocyte transfusion associated syndromes, and necrotizingenterocolitis.

[0015] Rhinovirus triggers the production of various proinflammatorycytokines, predominantly IL-8, which results in symptomatic illnessessuch as acute rhinitis (Winther et al., 1998, Am J Rhinol. 12, 17).

[0016] Other diseases that are effected by IL-8 include myocardialischemia and reperfusion, inflammatory bowel disease and many others.

[0017] The proinflammatory cytokine IL-6 has been implicated with theacute phase response. IL-6 is a growth factor in a number in oncologicaldiseases including multiple myeloma and related plasma cell dyscrasias(Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has alsobeen shown to be an important mediator of inflammation within thecentral nervous system. Elevated levels of IL-6 are found in severalneurological disorders including AIDS dementia complex, Alzheimer'sdisease, multiple sclerosis, systemic lupus erythematosus, CNS traumaand viral and bacterial meningitis (Gruol, et al., 1997, MolecularNeurobiology 15: 307). IL-6 also plays a significant role inosteoporosis. In murine models it has been shown to effect boneresorption and to induce osteoclast activity (Ershler et al., 1997,Development and Comparative Immunol. 21: 487). Marked cytokinedifferences, such as IL-6 levels, exist in vivo between osteoclasts ofnormal bone and bone from patients with Paget's disease (Mills, et al.,1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shownto be involved in cancer cachexia. The severity of key parameters ofcachexia can be reduced by treatment with anti IL-6 antibodies or withIL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther.1, 107). Several infectious diseases, such as influenza, indicate IL-6and IFN alpha as key factors in both symptom formation and in hostdefense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpressionof IL-6 has been implicated in the pathology of a number of diseasesincluding multiple myeloma, rheumatoid arthritis, Castleman's disease,psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997,Protein Sci. 6, 929). Compounds that interfered with the production ofcytokines including IL-6, and TNF were effective in blocking a passivecutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41,1050).

[0018] GM-CSF is another proinflammatory cytokine with relevance to anumber of therapeutic diseases. It influences not only proliferation anddifferentiation of stem cells but also regulates several other cellsinvolved in acute and chronic inflammation. Treatment with GM-CSF hasbeen attempted in a number of disease states including bum-woundhealing, skin-graft resolution as well as cytostatic and radiotherapyinduced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF alsoappears to play a role in the replication of human immunodeficiencyvirus (HIV) in cells of macrophage lineage with relevance to AIDStherapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41).Bronchial asthma is characterised by an inflammatory process in lungs.Involved cytokines include GM-CSF amongst others (Lee, 1998, J R CollPhysicians Lond 32, 56).

[0019] Interferon γ (IFN γ) has been implicated in a number of diseases.It has been associated with increased collagen deposition that is acentral histopathological feature of graft-versus-host disease (Parkman,1998, Curr Opin Hematol. 5, 22). Following kidney transplantation, apatient was diagnosed with acute myelogenous leukemia. Retrospectiveanalysis of peripheral blood cytokines revealed elevated levels ofGM-CSF and IFN γ. These elevated levels coincided with a rise inperipheral blood white cell count (Burke, et al., 1995, Leuk Lymphoma.19, 173). The development of insulin-dependent diabetes (Type 1) can becorrelated with the accumulation in pancreatic islet cells of T-cellsproducing IFN γ (Ablumunits, et al., 1998, J Autoimmun. 11, 73). IFN γalong with TNF, IL-2 and IL-6 lead to the activation of most peripheralT-cells prior to the development of lesions in the central nervoussystem for diseases such as multiple sclerosis (MS) and AIDS dementiacomplex (Martino et al., 1998, Ann Neurol. 43, 340). Atheroscleroticlesions result in arterial disease that can lead to cardiac and cerebralinfarction. Many activated immune cells are present in these lesions,mainly T-cells and macrophages. These cells produce large amounts ofproinflammatory cytokines such as TNF, IL-1 and IFN γ. These cytokinesare thought to be involved in promoting apoptosis or programmed celldeath of the surrounding vascular smooth muscle cells resulting in theatherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76).Allergic subjects produce mRNA specific for IFN γ following challengewith Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342).The expression of a number of cytokines, including IFN γ has been shownto increase following a delayed type hypersensitivity reaction thusindicating a role for IFN γ in atopic dermatitis (Szepietowski, et al.,1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologicstudies were performed in cases of fatal cerebral malaria. Evidence forelevated IFN γ amongst other cytokines was observed indicating a role inthis disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501).The importance of free radical species in the pathogenesis of variousinfectious diseases has been established. The nitric oxide synthesispathway is activated in response to infection with certain viruses viathe induction of proinflammatory cytokines such as IFN γ (Akaike, etal., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronicallyinfected with hepatitis B virus (HBV) can develop cirrhosis andhepatocellular carcinoma. Viral gene expression and replication in HBVtransgenic mice can be suppressed by a post-transcriptional mechanismmediated by IFN γ, TNF and IL-2 (Chisari, et al., 1995, Springer SeminImmunopathol. 17, 261). IFN γ can selectively inhibit cytokine inducedbone resorption. It appears to do this via the intermediacy of nitricoxide (NO) which is an important regulatory molecule in bone remodeling.NO may be involved as a mediator of bone disease for such diseases as:rheumatoid arthritis, tumor associated osteolysis and postmenopausalosteoporosis (Evans, et al., 1996, J Bone Miner Res. 11, 300). Studieswith gene deficient mice have demonstrated that the IL-12 dependentproduction of IFN γ is critical in the control of early parasiticgrowth. Although this process is independent of nitric oxide the controlof chronic infection does appear to be NO dependent (Alexander et al.,1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an importantvasodilator and convincing evidence exists for its role incardiovascular shock (Kilbourn, et al., 1997, Dis Mon. 43, 277). IFN γis required for progression of chronic intestinal inflammation in suchdiseases as Crohn's disease and inflammatory bowel disease (IBD)presumably through the intermediacy of CD4+ lymphocytes probably of theTH1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43). Anelevated level of serum IgE is associated with various atopic diseasessuch as bronchial asthma and atopic dermatitis. The level of IFN γ wasnegatively correlated with serum IgE suggesting a role for IFN γ inatopic patients (Teramoto et al., 1998, Clin Exp Allergy 28, 74).

[0020] WO 01/01986 discloses particular compounds alleged to having theability to inhibit TNF-alpha. Certain compounds disclosed in WO 01/01986are indicated to be effective in treating the following diseases:dementia associated with HIV infection, glaucoma, optic-neuropathy,optic neuritis, retinal ischemia, laser induced optic damage, surgery ortrauma-induced proliferative vitreoretinopathy, cerebral ischemia,hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbonmonoxide or manganese or cyanide poisoning, Huntington's disease,Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosisand other demyelinating diseases, amyotrophic lateral sclerosis, headand spinal cord trauma, seizures, convulsions, olivopontocerebellaratrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-relatedneuropathy, MERRF and MELAS syndromes, Leber's disease, Wernicke'sencephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia,hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyricaminoaciduria, sulfite oxidase deficiency, combined systems disease,lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drugaddiction, drug tolerance, drug dependency, depression, anxiety andschizophrenia. WO 02/32862 discloses that inhibitors of pro-inflammatorycytokines including TNFα are allegedly useful for treating acute andchronic inflammation in the lung caused by inhalation of smoke such ascigarette smoke. TNFα anatagonists are apparently also useful for thetreatment of endometriosis, see EP 1022027 A1. Infliximab, in clinicaltrials for RA, has also been indicated to be useful for treating variousinflammatory diseases including Behcet's disease, uveitis and ankylosingspondylitis. Pancreatitis may also be regulated by inflammatory mediatorproduction, see J Surg Res 2000 May 15 90(2)95-101; Shock 1998September. 10(3):160-75. p38MAP kinase pathway plays an role inB.burgdorferi-elicited infammation and may be useful in treatinginflammation induced by the Lyme disease agent. Anguita, J. et. al., TheJournal of Immunology, 2002,168:6352-6357.

[0021] Compounds which modulate release of one or more of theaforementioned inflammatory cytokines can be useful in treating diseasesassociated with release of these cytokines. For example, WO 98/52558discloses heteroaryl urea compounds which are indicated to be useful intreating cytokine mediated diseases. WO 99/23091 discloses another classof urea compounds which are useful as anti-inflammatory agents. WO99/32463 relates to aryl ureas amd their use in treating cytokinediseases and proteolytic enzyme mediated disease. WO 00/41698 disclosesaryl ureas said to be useful in treating p38 MAP kinase diseases.

[0022] Compounds active against p38 MAP kinase can also be useful fortreating various types of cancers as described in WO 03/068223.

[0023] U.S. Pat. No. 5,162,360 discloses N-substitutedaryl-N′-heterocyclic substituted urea compounds which are described asbeing useful for treating hypercholesterolemia and atheroclerosis.Di-substituted aryl and heteroaryl compounds are also disclosed in U.S.Pat. Nos. 6,080,763; 6,319,921; 6,297,381 and 6,358,945. The compoundsin the patents are alleged to possess anti-cytokine activity and aretherefore useful in treating diseases associated with inflammation.

[0024] The work cited above supports the principle that inhibition ofcytokine production will be beneficial in the treatment of cytokinemediated diseases. Therefore a need exists for small molecule inhibitorsfor treating these diseases with optimized efficacy, pharmacokinetic andsafety profiles.

BRIEF SUMMARY OF THE INVENTION

[0025] The work cited above supports the principle that inhibition ofcytokine production with small molecule compounds will be beneficial inthe treatment of various disease states.

[0026] It is therefore an object of the invention to provide compoundsof formula (I)

[0027] It is a further object of the invention to provide methods fortreating cytokine mediated diseases and pathological conditionsinvolving inflammation such as chronic inflammatory disease, using thenovel compounds of the invention.

[0028] It is yet a further object of the invention to providepharmaceutical compositions and processes of preparation of theabove-mentioned novel compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0029] In the broadest generic embodiment, there is provided compoundsof the formula (I)

[0030] wherein:

[0031] Ar¹ is an aromatic carbocycle substituted with one R¹, andwherein Ar¹ is independently substituted with two R² groups and whereinone R¹ and one R² on adjacent ring atoms optionally form a 5- or6-membered carbocyclic or heterocyclic ring;

[0032] R¹ is halogen, NO₂, NH₂, J-N(R^(a))—(CH₂)_(m)—, N(J)₂-(CH₂)_(m)—,NH₂C(O)—, J-N(R^(a))—C(O)—, J-S(O)_(m)—N(R^(a))—, J-N(R^(a))—S(O)_(m)—or heterocycle-(CH₂)_(m)— wherein the heterocyclic group is optionallysubstituted by C₁₋₅ alkyl;

[0033] Q is a N or CR^(p);

[0034] Y is >CR^(p)R^(v), —CR^(p)═C(R^(v))—, —O—, —N(R^(x))— or>S(O)_(m);

[0035] wherein R^(a), R^(p), R^(v), R^(x) and R^(y) are eachindependently hydrogen or C₁₋₅ alkyl;

[0036] X is —CH₂—, —N(R^(a))—, —O— or —S—;

[0037] W is N or CH;

[0038] each m is independently 0, 1 or 2;

[0039] J is chosen from C1-10 alkyl and carbocycle each optionallysubstituted by R^(b);

[0040] R² is chosen from C1-6 alkyl, C3-7 cycloalkyl optionallysubstituted by C1-5 alkyl, C1-4 acyl, aroyl, C1-4 alkoxy, each beingoptionally partially or fuilly halogenated, halogen, C1-6alkoxycarbonyl, carbocyclesulfonyl and —SO₂—CF₃;

[0041] each R³, R⁴ and R⁵ are independently chosen from hydrogen, C1-6alkyl and halogen;

[0042] R⁶ is optionally attached at a position ortho or meta to the Natom of the indicated ring, and is chosen from

[0043] a bond, —O—, —O—(CH₂)₁₋₅—, >C(O), —NH—, —C(O)—NH—, —S—, C₁₋₅alkyl branched or unbranched, C₂₋₅ alkenyl, C₁₋₃ acyl, C₁₋₃ alkyl(OH),heterocycle selected from morpholinyl, piperazinyl, piperidinyl,pyrrolidinyl and tetrahydrofuranyl, heteroaryl selected from pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,thienyl, furyl, isoxazolyl, thiazolyl, oxazolyl and isothiazolyl or aryleach alkyl, alkenyl, acyl, heterocycle, heteroaryl and aryl areoptionally substituted by one to three hydroxy, oxo, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₅ alkoxycarbonyl, —NR₇R₈ or NR₇R₈—C(O)—;

[0044] wherein each R₆ is further optionally covalently attached togroups chosen from:

[0045] hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, hydroxy,C₁₋₃ alkoxy, phenoxy, benzyloxy, arylC₀₋₄ alkyl, heteroaryl C₀₋₄ alkyland heterocycle C₀₋₄alkyl, each above-listed heterocycle, heteroaryl andaryl group is optionally substituted by one to three hydroxy, oxo, C₁₋₄alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, NR₇R₈—C(O)— or C₁₋₄ acyl;

[0046] each R₇ and R₈ are independently hydrogen, phenylC₀₋₃alkyloptionally subtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino, orR₇ and R₈ are C₁₋₂ acyl, benzoyl or C₁₋₅ branched or unbranched alkyloptionally substituted by C₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃ alkylamino; and

[0047] R^(b) is chosen from hydrogen, C1-5 alkyl, hydroxyC1-5 alkyl,C2-5 alkenyl, C2-5 alkynyl, carbocycle, heterocycle, heteroaryl, C1-5alkoxy, C1-5 alkylthio, amino, C1-5 alkylamino, C1-5 dialkylamino, C1-5acyl, C1-5 alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, each of theaforementioned are optionally partially or fully halogenated, or R^(b)is chosen from C1-5 alkylsulphonylamino, hydroxy, oxo, halogen, nitroand nitrile;

[0048] or the pharmaceutically acceptable salts, acids, esters orisomers thereof.

[0049] In another embodiment, there are provided compounds of theformula (I) as described above and wherein

[0050] Y is —O—, —S—, —NH—, —N(CH₂CH₃)— or —N(CH₃)—;

[0051] X is —N(R^(a))—, or —O—;

[0052] Q is CH;

[0053] J is chosen from C1-10 alkyl, aryl or C3-7 cycloalkyl eachoptionally substituted by R^(b);

[0054] R₂ is independently chosen from C1-6 alkyl, C3-6 cycloalkyloptionally substituted by C1-3 alkyl, acetyl, aroyl, C1-5 alkoxy, eachbeing optionally partially or fully halogenated, halogen,methoxycarbonyl, phenylsulfonyl and —SO₂—CF₃;

[0055] each R³, R⁴ and R⁵ are hydrogen;

[0056] R^(b) is chosen from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5alkynyl, C3-8 cycloalkylC0-2 alkyl, aryl, C1-5 alkoxy, C1-5 alkylthio,amino, C1-5 alkylamino, C1-5 dialkylamino, C1-5 acyl, C1-5alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, C1-5 sulphonylamino,hydroxy, halogen, trifluoromethyl, nitro, nitrile or R^(b) is chosenfrom; heterocycle chosen from pyrrolidinyl, pyrrolinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone,dioxalanyl, piperidinyl, piperazinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone,1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl, pentamethylenesulfide, pentamethylene sulfoxide, pentamethylene sulfone,tetramethylene sulfide, tetramethylene sulfoxide and tetramethylenesulfone and heteroaryl chosen from aziridinyl, thienyl, furanyl,isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl,pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl,indazolyl, triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl,pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl,oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl.

[0057] In yet another embodiment, there are provided compounds of theformula (I) as described immediately above and wherein

[0058] Ar¹ is chosen from phenyl, naphthyl, tetrahydronaphthyl, indanyland indenyl, each Ar¹ is optionally substituted with one R¹, andindependently substituted with two R² groups;

[0059] Y is —O—, —S— or —N(CH₃)—;

[0060] R⁶ is present, and is chosen from

[0061] a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branchedor unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), heterocycle selected frommorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl andtetrahydrofuranyl, or aryl chosen from phenyl and naphthyl, each alkyl,alkenyl, heterocycle and aryl are optionally substituted by one to threehydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl amino, amino orC₁₋₅ alkoxycarbonyl;

[0062] wherein each R₆ is further optionally covalently attached togroups chosen from:

[0063] hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, hydroxy,C₁₋₃ alkoxy, phenoxy, benzyloxy, phenylC₀₋₄ alkyl, piperazinylC₀₋₄alkyl, piperidinyl C₀₋₄alkyl, pyrrolidinylC₀₋₄ alkyl, morpholinylC₀₋₄alkyl, tetrahydrofuranylC₀₋₄ alkyl, triazolyl C₀₋₄alkyl, imidazolylC₀₋₄alkyl and pyridinyl C₀₋₄alkyl, each abovelisted heterocycle,heteroaryl and phenyl group is optionally substituted by one to threehydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, —NR₇R₈,NR₇R₈—C(O)— or C₁₋₄ acyl;

[0064] each R₇ and R₈ are independently hydrogen, phenylC₀₋₃alkyloptionally subtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino, orR₇ and R₈ are C₁₋₂ acyl, benzoyl or C₁₋₅ branched or unbranched alkyloptionally substituted by C₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃ alkylamino.

[0065] In yet another embodiment, there are provided compounds of theformula (I) as described immediately above and wherein

[0066] X is —O—;

[0067] Y is —N(CH₃)—;

[0068] J is C1-10 alkyl optionally substituted by R^(b);

[0069] R₂ is independently chosen from C1-6 alkyl, C3-6 cycloalkyloptionally substituted by C1-3 alkyl and C1-5 alkoxy, each beingoptionally be partially or fully halogenated;

[0070] R⁶ is chosen from

[0071] a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branchedor unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), heterocycle selected frommorpholinyl, piperazinyl, piperidinyl and pyrrolidinyl or phenyl, eachalkyl, alkenyl, heterocycle and phenyl are optionally substituted by oneto three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl amino,amino or C₁₋₅ alkoxycarbonyl;

[0072] wherein each R₆ is further optionally covalently attached togroups chosen from:

[0073] hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl,benzyloxy, phenylC₀₋₄ alkyl, piperazinylC₀₋₄ alkyl, piperidinylC₀₋₄alkyl, pyrrolidinylC₀₋₄ alkyl, morpholinylC₀₋₄ alkyl, triazolylC₀₋₄alkyl, imidazolyl C₀₋₄alkyl and pyridinyl C₀₋₄alkyl, eachabove-listed heterocycle, heteroaryl and phenyl group is optionallysubstituted by one to three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅alkoxycarbonyl, amino, NR₇R₈—C(O)— or C₁₋₄ acyl;

[0074] each R₇ and R₈ are independently hydrogen, phenylC₀₋₂alkyloptionally subtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino, orR₇ and R₈ are C₁₋₅ branched or unbranched alkyl optionally substitutedby C₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃ alkyl amino;

[0075] R^(b) is chosen from hydrogen, C1-5 alkyl, C3-7 cycloalkylC0-2alkyl, aryl, C1-5 alkoxy, amino, C1-5 alkylamino, C1-3 dialkylamino,C1-3 acyl, C1-5 alkoxycarbonyl, C1-3 acyloxy, C1-3 acylamino, C1-3sulphonylamino, hydroxy, halogen, trifluoromethyl, nitro, nitrile;

[0076] or R^(b) is chosen from pyrrolidinyl, pyrrolinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone,piperidinyl, piperazinyl, piperidinonyl, tetrahydropyrimidonyl,aziridinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl,pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl.

[0077] In yet still another embodiment, there are provided compounds ofthe formula (I) as described immediately above and wherein

[0078] Ar¹ is formula (A) or (B)

[0079]  wherein:

[0080] when Ar¹ is formula (A) then:

[0081] R¹ is NH₂, J-N(R^(a))—(CH₂)_(m)—, NH₂C(O)—, J-N(R^(a))—C(O)—,J-S(O)₂—N(R^(a))—, J-N(R^(a))—S(O)₂— or heterocycle-(CH₂)₁₋₂— whereinthe heterocycle is chosen from pyrrolidinyl, morpholinyl and piperazinyleach optionally substituted by C1-4 alkyl, and

[0082] J is C₁₋₅ alkyl optionally substituted by R^(b); or

[0083] when Ar¹ is formula (B) then:

[0084] R¹ is hydrogen or halogen;

[0085] R₂ is independently chosen from C1-5 alkyl, C3-6 cycloalkyloptionally substituted by C1-3 alkyl and C1-5 alkoxy, each beingoptionally partially or fully halogenated;

[0086] R⁶ is chosen from

[0087] a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branchedor unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), heterocycle selected frommorpholinyl, piperazinyl, piperidinyl and pyrrolidinyl or phenyl, eachalkyl, alkenyl, heterocycle and phenyl are optionally substituted by oneto three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl amino,amino or C₁₋₅ alkoxycarbonyl;

[0088] wherein each R₆ is further optionally covalently attached togroups chosen from:

[0089] hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl,benzyloxy, phenylC₀₋₄ alkyl, piperazinyl, piperazinylC₁₋₂ alkyl,piperidinyl, piperidinyl C₁₋₂alkyl, pyrrolidinyl, pyrrolidinyl C₁₋₂alkyl, morpholinyl, morpholinylC₁₋₂ alkyl, triazolyl, triazolylC₁₋₂alkyl, imidazolyl, imidazolyl C₁₋₂alkyl, pyridinyl and pyridinylC₁₋₂alkyl, each above-listed heterocycle, heteroaryl and phenyl group isoptionally substituted by one to three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃alkoxy, C₁₋₅ alkoxycarbonyl, amino, NR₇R₈—C(O)— or C₁₋₄ acyl.

[0090] In yet still another embodiment, there are provided compounds ofthe formula (I) as described immediately above and wherein

[0091] Ar¹ is formula (A) or (B)

[0092]  and R² is chosen from

[0093]  and

[0094] when Ar¹ is formula (A) then:

[0095] when R¹ is J-S(O)₂—N(R^(a))— or J-N(R^(a))—S(O)₂— then J is C₁₋₃alkyl; and

[0096] when R¹ is NH₂, J-N(R^(a))—(CH₂)_(m)—, NH₂C(O)—,J-N(R^(a))—C(O)—, or heterocycle-(CH₂)₁₋₂— wherein the heterocycle ischosen from pyrrolidinyl, morpholinyl, piperazinyl orC1-4alkylpiperazinyl, then

[0097] J is C1-3 alkyl optionally substituted by R^(b).

[0098] In yet another embodiment, there are provided compounds of theformula (I) as described immediately above and wherein

[0099] R^(b) is chosen from hydrogen, C1-5 alkyl, C3-6 cycloalkylC0-2alkyl, phenyl, C1-5 alkoxy, amino, C1-5 alkylamino, C1-3 dialkylamino,C1-3 acyl, C1-5 alkoxycarbonyl, C1-3 acyloxy, C1-3 acylamino, hydroxy,halogen;

[0100] or R^(b) is chosen from morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperidinyl,piperidinonyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl.

[0101] In yet another embodiment, there are provided compounds of theformula (I) as described immediately above and wherein

[0102] R^(b) is chosen from amino, C1-5 alkylamino, C1-3 dialkylamino;

[0103] or R^(b) is chosen morpholinyl, piperidinyl and pyridinyl.

[0104] In yet still another embodiment, there are provided compounds ofthe formula (I) as described immediately above and wherein

[0105] Ar¹ is formula (A).

[0106] In yet still another embodiment, there are provided compounds ofthe formula (I) as described above and wherein

[0107] Ar¹ is formula (B).

[0108] In yet another embodiment, there are provided compounds of theformula (I) as described above and wherein

[0109] Ar¹ is

[0110] The following are representative compounds of the invention whichhave been made according to the general schemes and working examplesbelow: TABLE I

1-Methyl-7-(pyrimidin-4-yloxy)-1H- indole-2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

7-(2-Methylamino-pyrimidin-4-yloxy)- 1H-indole-2-carboxylic acid(5-tert-butyl- 3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid (5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid (5- tert-butyl-2-methoxy-phenyl)-amide

7-[2-(2-Diethylamino-ethylamino)-pyrimidn-4-yloxy]-1-methyl-1H-indole-2- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-(2-Cyclopropylamino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(4-Methoxy-benzylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2- carboxylic acid(5-tert-butyl-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl- ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(3-Dimethylamino-propylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2- carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(3-Dimethylamino-2,2-dimethyl- propylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

7-(2-Dimethylamino-pyrimidin-4-yloxy)- 1-methyl-1H-indole-2-carboxylicacid (5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

1-Methyl-7-(6-methyl-2-methylamino- pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl- ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(piperidin-4-ylamino)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

4-{4-[2-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indole-7-yloxy]-pyrimidin-2-ylamino}-piperidine- 1-carboxylic acid tert-butylester

7-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-pyrimidin-4-yloxy}-1-methyl-1H- indole-2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[6-methyl-2-(4-methyl- piperiazin-1-yl)pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methaesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Dimethylamino-ethoxy)- pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3- methaesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Dimethylamino-ethoxy)- pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl-ethoxy)-pyrimidin-4-yloxy]-1H-indole-2- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethoxy)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(1-methyl-pipidin-4-yloxy)-pyrimidin-4-yloxy]-1H-indole-2- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(2-Dimethylamino-ethoxy)-6-methyl-pyrimidin-4-yloxy]-1-methyl-1H-indole-2- carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(2-methylcarbamoyl-pyridin- 4-yloxy)-1H-indole-2-carboxylicacid [5- tert-butyl-3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]- amide

7-[2-(2-Dimethylamino-ethylcarbamoyl)-pyridin-4-yloxy]-1-methyl-1H-indole-2- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid [5- tert-butyl-3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]- amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid ]5- tert-butyl-2-methoxy-3-(2-morpholin-4-yl-ethylcarbamoyl)-phenyl]-amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid (5- tert-butyl-3-carbamoyl--2-methoxy- phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid (5- tert-butyl-2-methoxy-3-methylcarbamoyl- phenyl)-amide

1-Methyl-7-(2-vinyl-pyrimidin-4-yloxy)- 1H-indole-2-carboxylic acid(5-tert-butyl- 3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(1,2-Dihydroxy-ethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(morpholin-4-ylamino)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl- pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyrimidin-4-yloxy]-1H-indole- 2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

7-(2-Dimethylaminomethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(2-methanecarbamoyl-pyridin- 4-yloxy)-1H-indole-2-carboxylicacid (5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

7-(2-Benzyloxymethyl-pyridin-4-yloxy)- 1-methyl-1H-indole-2-carboxylicacid (5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid (5- tert-butyl-2-methoxy-3-morpholin-4- ylmethyl-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid [5- tert-butyl-2-methoxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid (5- tert-butyl-3-dimethylaminoethyl-2- methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid (3- amino-5-tert-butyl-2-methoxy-phenyl)- amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid (5- tert-butyl-3-dibenzylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid (5- tert-butyl-2-methoxy-2-methylsulfamoyl- phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2- carboxylic acid(5-tert-butyl-3- [1,3]dioxolan-2-yl-2-methoxy-phenyl)- amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-2-methoxy-3-methylaminomethyl-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-2-methoxy-3-pyrrolidin-1-ylmethyl-phenyl)-amide

1-Methyl-7-{2-[methyl-(1-methyl- piperidin-4-yl)-amino]-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

7-(2-Hydroxymethyl-pyridin-4-yloxy)-1- methyl-1H-indole-2-carboxylicacid (5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide and

1-Methyl-7-(2-methylamino-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid [5- tert-butyl-2-methoxy-3-(2-morpholin-4-yl-ethylamino)-phenyl]-amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole- 2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(2-piperazin-1-yl-pyrimidin-4- yloxy)-1H-indole-2-carboxylicacid (5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

1-Methyl-7-(pyrimidin-4-yloxy)-1H- indole-2-carboxylic acid [3-methanesulfonylamino-2-methoxy-5-(2- methyl-cyclopropyl)-phenyl]-amide

1-Methyl-7-[2-(5-methyl-2,5-diaza- bicyclo[2.2.1]hept-2-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

7-[2-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2- carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

7-(2-Methoxy-pyrimidin-4-yloxy)-1- methyl-1H-indole-2-carboxylic acid(5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

7-[2-(4-tert-Butyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2- carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-{2-[2-(4-methyl-piperazin-1-yl)-ethyl]-pyrimidin-4-yloxy}-1H-indole- 2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl-ethyl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Dimethylamino-ethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)- amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)- amide

7-{2-[2-(4-tert-Butyl-piperazin-1-yl)-ethyl]-pyrimidin-4-yloxy}-1-methyl-1H- indole-2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(4-tert-Butyl-piperazin-1-ylmethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2- carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl- pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2,6-Dimethyl-pyridin-4-yloxy)-1- methyl-1H-indole-2-carboxylic acid(5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

7-(2-Ethyl-pyridin-4-yloxy)-1-methyl-1H- indole-2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidin-4-yloxy]-1H-indole-2- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-(2-Amino-pyrimidin-4-yloxy)-1-methyl- 1H-indole-2-carboxylic acid(5-tert-butyl- 3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(2-piperidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyridin-4-yloxy]-1H-indole-2- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole- 2-carboxylic acid(5-tert-butyl-3-{[(2- dimethylamino-ethyl)-methyl-amino]-methyl}-2-methoxy-phenyl)-amide

7-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-pyrimidin-4-yloxy)-1- methyl-1H-indole-2-carboxylic acid(5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3-carbamoyl- 2-methoxy-phenyl)-amide

1-Methyl-7-[2-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridin-4- yloxy]-1H-indole-2-carboxylicacid (5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl- [1,4]diazepan-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert- butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-[1,4]Diazepan-1-ylpyridin-4- yloxy)-1-methyl-1-H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-piperazin-1-yl-pyridin- 4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino- 2-methoxy-phenyl)-amide

1-trideuterio-7-(2-piperazin-1-yl- pyridin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(Hexahydro-pyrrolo[1,2- a]pyrazin-2-yl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-trideuterio-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2- carboxylic acid [3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-amide

7-[2-((S)-3-Dimethylamino-pyrrolidin-1-yl)-pyridin-4-yloxy]-1-methyl-1H- indole-2-carboxylic acid [3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-amide

7-[2-((S)-3-Dimethylamino-pyrrolidin-1-yl)-pyridin-4-yloxy]-1-methyl-1H- indole-2-carboxylic acid [3-methanesulfonylamino-2-methoxy-5- (1-methyl-cyclopropyl)-phenyl]-amide

1-Methyl-7-[2-(4-methyl-piperazine-1-carbonyl)-pyridin-4-yloxy]-1H-indole- 2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(piperazine-1- carbonyl)-pyridin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

[0111] or the pharmaceutically acceptable salts, acids, esters orisomers thereof.

[0112] Preferred compounds of the invention are listed in table II.TABLE II

1-Methyl-7-(pyrimidin-4-yloxy)-1H- indole-2-carboxylic acid(5-tert-butyl- 3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1- yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- carbamoyl-2-methoxy-phenyl)-amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl- pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-{[(2-Dimethylamino-ethyl)- methyl-amino]-methyl}-pyrimidin-4-yloxy)-1-methyl-1H-indole-2- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(pyridin-4-yloxy)-1H- indole-2-carboxylic acid (5-tert-butyl-3-{[(2-dimethulamino-ethyl)-methyl- amino]-methyl}-2-methoxy-phenyl)-amide

7-[2-(4-tert-Butyl-piperazin-1- ylmethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Dimethylaminomethyl-pyridin-4- yloxy)-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

7-{2-[2-(4-tert-Butyl-piperazin-1-yl)-ethyl]-pyrimidin-4-yloxy}-1-methyl- 1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl- ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino- pyrimidin-4-yloxy)-1H-indole-2- carboxylicacid (5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)- pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl- ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1- yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl- ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(3-Dimethylamino-propylamino)- pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(3-Dimethylamino-2,2-dimethyl- propylamino)-pyrimidn-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Dimethylamino-pyrimidin-4- yloxy)-1-methyl-1H-indole-2- carboxylicacid (5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(6-methyl-2-methylamino- pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl- ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(piperidin-4-ylamino)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

7-{2-[(2-Dimethylamino-ethyl)- methyl-amino]-pyrimidin-4-yloxy}-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-{2-[2-(4-methyl-piperazin-1-yl)-ethyl]-pyrimidin-4-yloxy}-1H- indole-2-carboxylic acid(5-tert-butyl- 3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(2-Dimethylamino-ethoxy)- pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl- ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl- ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-methyl-piperidin-4-yloxy)-pyrimidin-4-yloxy]-1H-indole- 2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(4-tert-Butyl-piperazin-1-yl)- pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(2-methylcarbamoyl- pyridin-4-yloxy)-1H-indole-2- carboxylicacid [5-tert-butyl-3-(2- dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide

7-[2-(2-Dimethylamino- ethylcarbamoyl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino- pyrimidin-4-yloxy)-1H-indole-2- carboxylicacid [5-tert-butyl-3-(2- dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide

1-Methyl-7-(2-methylamino- pyrimidin-4-yloxy)-1H-indole-2- carboxylicacid [5-tert-butyl-2- methoxy-3-(2-morpholin-4-yl-ethylcarbamoyl)-phenyl]-amide

1-Methyl-7-(2-methylamino- pyrimidin-4-yloxy)-1H-indole-2- carboxylicacid (5-tert-butyl-3- carbamoyl-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino- pyrimidin-4-yloxy)-1H-indole-2- carboxylicacid (5-tert-butyl-2- methoxy-3-methylcarbamoyl-phenyl)- amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl- pyridin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(1,2-Dihydroxy-ethyl)-pyrimidin- 4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(morpholin-4-ylamino)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonyl-2-methoxy-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl- pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl- pyridin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1- ylmethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-(2-Dimethylaminomethyl-pyridin-4- yloxy)-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylcarbamoyl- pyridin-4-yloxy)-1H-indole-2- carboxylicacid (5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(2-piperidin-1-ylmethyl- pyridin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

1-methyl-7-(2-methylamino- pyrimidin-4-yloxy)-1H-indole-2- carboxylicacid (5-tert-butyl-2- methoxy-3-morpholin-4-ylmethyl- phenyl)-amide

1-Methyl-7-(2-methylamino- pyrimidin-4-yloxy)-1H-indole-2- carboxylicacid [5-tert-butyl-2- methoxy-3-(4-methyl-piperazin-1-ylmethyl)phenyl]-amide

1-Methyl-7-(2-methylamino- pyrimidin-4-yloxy)-1H-indole-2- carboxylicacid (5-tert-butyl-3- dimethylaminomethyl-2-methoxy- phenyl)-amide

1-Methyl-7-(2-methylamino- pyrimidin-4-yloxy)-1H-indole-2- carboxylicacid (3-amino-5-tert-butyl- 2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyridin-4-yloxy]-1H-indole- 2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1- yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-2- methoxy-3-methylaminomethyl-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1- yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-2- methoxy-3-pyrrolidin-1-ylmethyl-phenyl)-amide

1-Methyl-7-{2-[methyl-(1-methyl- piperidin-4-yl)-amino]-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Hydroxymethyl-pyridin-4-yloxy)- 1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino- 2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino- pyrimidin-4-yloxy)-1H-indole-2- carboxylicacid [5-tert-butyl-2- methoxy-3-(2-morpholin-4-yl-ethylamino)-phenyl]-amide and

1-Methyl-7-(pyridin-4-yloxy)-1H- indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

[0113] or the pharmaceutically acceptable salts, acids, esters orisomers thereof.

[0114] The following are representative compounds of the invention whichcan be made according to the general schemes and working examples below:TABLE III

7-(pyrimidin-4-yloxy)-benzo[b]thiophene- 2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

7-(Pyrimidin-4-yloxy)-1H-indole-2- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-(Pyrimidin-4-yloxy)-benzofuran-2- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(pyrimidin-4-ylsulfanyl)-1H- indole-2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(pyrimidin-4-ylamino)-1H- indole-2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-(pyridin-3-yloxy)-1H-indole- 2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

7-(2-Benzylamino-pyrimidin-4-yloxy)-1- methyl-1H-indole-2-carboxylicacid (5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

1-Methyl-7-{2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-1H-indole-2- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(2-Imidazol-1-yl-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole- 2-carboxyli acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(2-[1,2,3]triazol-1-yl- ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(3-Dimethylamino-propylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole- 2-carboxylic acid[2-methoxy-5-(2,2,2- trifluoro-1-trifluoromethyl-ethyl)-phenyl]- amide

7-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-pyrimidin-4-yloxy}-1-methyl-1H- indole-2-carboxylic acid(4-chloro-2- methoxy-5-trifluoromethyl-phenyl)-amide

7-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (4-chloro-2-methoxy-5- trifluoromethyl-phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole- 2-carboxylic acid 92-methoxy-5-trifluoromethoxy-phenyl)-amide

7-[2-(4-Dimethylamino-piperidin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole- 2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(3-Dimethylamino-pyrrolidin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole- 2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(1-methyl-piperidin-4-ylamino)-pyrimidin-4-yloxy]-1H-indole- 2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(1-Acetyl-piperidin-4-ylamino)-pyrimidin-4-ylozy]-1-methyl-1H-indole- 2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethoxy)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)- amide

7-[2-(2-Imidazol-1-yl-ethoxy)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-[2-(2-Imidazol-1-yl-ethoxy)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid (4-chloro-2-methoxy-5-trifluoromethyl-phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole- 2-carboxylic acid(5-tert-butyl-2-methoxy- 3-methylcarbamoyl-phenyl)-amide

7-(2-Amino-pyrimidin-4-yloxy)-1-methyl- 1H-indole-2-carboxylic acid(5-tert-butyl- 3-carbamoyl-2-methoxy-phenyl)-amide

7-(2-Amino-pyrimidin-4-yloxy)-1-methyl- 1H-indole-2-carboxylic acid[5-tert-butyl- 3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole- 2-carboxylic acid(5-tert-butyl-3- dimethylaminomethyl-2-methoxy- phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole- 2-carboxylic acid(5-tert-butyl-2-methoxy- 3-pyrrolidin-1-ylmethyl-phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-mnethyl-1H-indole- 2-carboxylic acid(5-tert-butyl-2-methoxy- 3-morpholin-4-ylmethyl-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl- pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (4-chloro-2-methoxy-5- trifluoromethyl-phenyl)-amide

7-[2-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-1-methyl- 1H-indole-2-carboxylic acid(5-tert-butyl- 3-methanesulfonylamino-2-methoxy- phenyl)-amide

7-(2-Carbamoyl-pyrimidin-4-yloxy)-1- methyl-1H-indole-2-carboxylic acid(5- tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl- pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (2-methoxy-3-morpholin-4-ylmethyl-5-trifluoromethyl-phenyl)- amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (2-methoxy-3-morpholin-4-ylmethyl-5-trifluoromethyl-phenyl)- amide

1-Methyl-7-(2-morpholin-4-ylmethyl- pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)- amide

7-(1′-tert-Butyl-1′,2′,3′,4′,5′,6′-hexahydro-]2,4′]bipyridinyl-4-yloxy)-1-methyl-1H- indole-2-carboxylic acid (3-methanesulfonylamino-2-methoxy-5- trifluoromethyl-phenyl)-amide

1-Methyl-7-(2-methylaminomethyl- pyridin-4-yloxy)-1H-indole-2-carboxylicacid (3-methanesulfonylamino-2- methoxy-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylic acid(2-methoxy-3-morpholin-4-ylmethyl- 5-trifluoromethyl-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (3-dimethylaminomethyl-2-methoxy-5-trifluoromethyl-phenyl)- amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl- pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid (2-methoxy-3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl)- amide

7-(2-Dimethylaminomethyl-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid[2-methoxy-3-(4-methyl-piperazin-1- ylmethyl)-5-trifluoromethyl-phenyl]-amide

7-(2-Dimethylaminomethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

7-(2-Dimethylaminomethyl-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyrimidin-4-yloxy]-1H-indole- 2-carboxylic acid (3-methanesulfonylamino-2-methoxy-5- trifluoromethyl-phenyl)-amide

7-(2-Dimethylaminomethyl-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid [3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)- phenyl]-amide

1-Methyl-7-[2-(1-methyl-piperidin-4-yl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(1-Cyclopropyl-piperidin-4-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole- 2-carboxylic acid(5-tert-butyl-3- methanesulfonylamino-2-methoxy- phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)- pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid (3-dimethylaminomethyl-2-methoxy-5-trifluoromethyl-phenyl)- amide

1-Methyl-7-[2-(1-methyl-pyrrolidin-3-ylamino)-pyridin-4-yloxy]-1H-indole-2- carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenyl)-amide

[0115] or the pharmaceutically acceptable salts, acids, esters orisomers thereof.

[0116] In all the compounds disclosed hereinabove in this application,in the event the nomenclature is in conflict with the structure, itshall be understood that the compound is defined by the structure.

[0117] Of particular importance according to the invention are compoundsof formula (I), wherein Ar₁, X, Y, Q, W, R³, R⁴, R⁵, R⁶ and R^(y) havethe meaning indicated, for use as pharmaceutical compositions with ananti-cytokine activity.

[0118] The invention also relates to the use of a compound of formula(I), wherein Ar₁, X, Y, Q, W, R³, R⁴, R⁵, R⁶ and R^(y) have the meaningindicated, for preparing a pharmaceutical composition for the treatmentand/or prevention of a cytokine mediated disease or condition.

[0119] The invention also relates to pharmaceutical preparations,containing as active substance one or more compounds of formula (I),wherein Ar₁, X, Y, Q, W, R³, R⁴, R⁵, R⁶ and R^(y) have the meaningsindicated, or the pharmaceutically acceptable derivatives thereof,optionally combined with conventional excipients and/or carriers.

[0120] Compounds of the invention also include theirisotopically-labelled forms. An isotopically-labelled form of an activeagent of a combination of the present invention is identical to saidactive agent but for the fact that one or more atoms of said activeagent have been replaced by an atom or atoms having an atomic mass ormass number different from the atomic mass or mass number of said atomwhich is usually found in nature. Examples of isotopes which are readilyavailable commercially and which can be incorporated into an activeagent of a combination of the present invention in accordance with wellestablished procedures, include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine and chlorine, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. An active agent ofa combination of the present invention, a prodrug thereof, or apharmaceutically acceptable salt of either which contains one or more ofthe above-mentioned isotopes and/or other isotopes of other atoms iscontemplated to be within the scope of the present invention.

[0121] The invention includes the use of any compounds of describedabove containing one or more asymmetric carbon atoms may occur asracemates and racemic mixtures, single enantiomers, diastereomericmixtures and individual diastereomers. All such isomeric forms of thesecompounds are expressly included in the present invention. Eachstereogenic carbon may be in the R or S configuration, or a combinationof configurations.

[0122] Some of the compounds of formula (I) can exist in more than onetautomeric form. The invention includes methods using all suchtautomers.

[0123] All terms as used herein in this specification, unless otherwisestated, shall be understood in their ordinary meaning as known in theart. For example, “C₁₋₄alkoxy” is a C₁₋₄alkyl with a terminal oxygen,such as methoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl and alkynylgroups shall be understood as being branched or unbranched wherestructurally possible and unless otherwise specified. Other morespecific definitions are as follows:

[0124] The term “aroyl” as used in the present specification shall beunderstood to mean “benzoyl” or “naphthoyl”.

[0125] Carbocycles include hydrocarbon rings containing from three totwelve carbon atoms. These carbocycles may be either aromatic eitheraromatic or non-aromatic ring systems. The non-aromatic ring systems maybe mono- or polyunsaturated. Preferred carbocycles include but are notlimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl,indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl,naphthyl, decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl.Certain terms for cycloalkyl such as cyclobutanyl and cyclobutyl shallbe used interchangeably.

[0126] The term “heterocycle” refers to a stable nonaromatic 4-8membered (but preferably, 5 or 6 membered) monocyclic or nonaromatic8-11 membered bicyclic heterocycle radical which may be either saturatedor unsaturated. Each heterocycle consists of carbon atoms and one ormore, preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygenand sulfur. The heterocycle may be attached by any atom of the cycle,which results in the creation of a stable structure. Unless otherwisestated, heterocycles include but are not limited to, for examplepyrrolidinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinylsulfoxide, thiomorpholinyl sulfone, dioxalanyl, piperidinyl,piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl,tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene sulfoxide,pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxideand tetramethylene sulfone.

[0127] The term “heteroaryl” shall be understood to mean an aromatic 5-8membered monocyclic or 8-11 membered bicyclic ring containing 1-4heteroatoms such as N, O and S. Unless otherwise stated, suchheteroaryls include aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl,thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl,indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl,quinolinyl, quinazolinyl, naphthyridinyl, indazolyl, triazolyl,pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl,pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl andimidazo[4,5-b]pyridinyl.

[0128] The term “heteroatom” as used herein shall be understood to meanatoms other than carbon such as O, N, S and P.

[0129] In all alkyl groups or carbon chains one or more carbon atoms canbe optionally replaced by heteroatoms: O, S or N, it shall be understoodthat if N is not substituted then it is NH, it shall also be understoodthat the heteroatoms may replace either terminal carbon atoms orinternal carbon atoms within a branched or unbranched carbon chain. Suchgroups can be substituted as herein above described by groups such asoxo to result in defintions such as but not limited to: alkoxycarbonyl,acyl, amido and thioxo.

[0130] The term “aryl” as used herein shall be understood to meanaromatic carbocycle or heteroaryl as defined herein. Each aryl orheteroaryl unless otherwise specified includes it's partially or fullyhydrogenated derivative. For example, quinolinyl may includedecahydroquinolinyl and tetrahydroquinolinyl, naphthyl may include it'shydrogenated derivatives such as tetrahydranaphthyl. Other partially orfully hydrogenated derivatives of the aryl and heteroaryl compoundsdescribed herein will be apparent to one of ordinary skill in the art.

[0131] As used herein, “nitrogen” and “sulfur” include any oxidized formof nitrogen and sulfur and the quaternized form of any basic nitrogen.For example, for an —S—C₁₋₆ alkyl radical, unless otherwise specified,this shall be understood to include —S(O)—C₁₋₆ alkyl and —S(O)₂—C₁₋₆alkyl.

[0132] The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine, preferablyfluorine. The definitions “partially or fully halogenated”; partially orfully fluorinated; “substituted by one or more halogen atoms”, includesfor example, mono, di or tri halo derivatives on one or more carbonatoms. For alkyl, a nonlimiting example would be —CH₂CHF₂, —CF₃ etc.

[0133] The compounds of the invention are only those which arecontemplated to be ‘chemically stable’ as will be appreciated by thoseskilled in the art. For example, a compound which would have a ‘danglingvalency’, or a ‘carbanion’ are not compounds contemplated by theinventive methods disclosed herein.

[0134] The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester, or any othercompound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound useful for the invention,or a pharmacologically active metabolite or pharmacologically activeresidue thereof. A pharmacologically active metabolite shall beunderstood to mean any compound of the invention capable of beingmetabolized enzymatically or chemically. This includes, for example,hydroxylated or oxidized derivative compounds of the formula (I).

[0135] Pharmaceutically acceptable salts include those derived frompharmaceutically acceptable inorganic and organic acids and bases.Examples of suitable acids include hydrochloric, hydrobromic, sulfuric,nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic,salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric,methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric andbenzenesulfonic acids. Other acids, such as oxalic acid, while notthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsand their pharmaceutically acceptable acid addition salts. Salts derivedfrom appropriate bases include alkali metal (e.g., sodium), alkalineearth metal (e.g., magnesium), ammonium and N—(C₁-C₄ alkyl)₄ ⁺ salts.

[0136] In addition, within the scope of the invention is use of prodrugsof compounds of the formula (I). Prodrugs include those compounds that,upon simple chemical transformation, are modified to produce compoundsof the invention. Simple chemical transformations include hydrolysis,oxidation and reduction. Specifically, when a prodrug is administered toa patient, the prodrug may be transformed into a compound disclosedhereinabove, thereby imparting the desired pharmacological effect.

GENERAL SYNTHETIC METHODS

[0137] The invention additionally provides for methods of making thecompounds of the formula (I). The compounds of the invention may beprepared by the general methods and examples presented below, andmethods known to those of ordinary skill in the art. Further referencein this regard may be made to U.S. Pat. No. 6,358,945, U.S. applicationSer. Nos. 09/714,539, 09/834,797, 10/120,028, 10/143,322 and 10/147,675.U.S. application Ser. No. 10/264,689 teaches additional methods forpreparation of sulfonamide intermediates. Each of the aforementionedU.S. cases are incorporated in their entirety. In all schemes, unlessotherwise specified, Ar¹, X, Y, W and R³-R⁶ in the formulas shown belowshall have the meanings defined for these groups in the definition ofthe formula (I) of the invention, described hereinabove. Intermediatesused in the syntheses below are either commercially available or easilyprepared by methods known to those skilled in the art. Reaction progressmay be monitored by conventional methods such as thin layerchromatography (TLC). Intermediates and products may be purified bymethods known in the art, including column chromatography, HPLC orrecrystallization.

[0138] Compounds of the invention where Q is a carbon atom, may beprepared as described in Schemes I and II. Compounds of the inventionwherein Q is a nitrogen atom, may be prepared by analogous methods whichwill be apparent to one of ordinary skill in the art.

[0139] As illustrated in Scheme I an amine bearing Ar¹ is coupled withcarboxylic acid III, where P is a protecting group, using standardcoupling conditions known in the art (see for example M. Bodanszky,1984, The Practice of Peptide Synthesis, Springer-Verlag). For example,one may couple III and II by treating with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC)followed by 1-hydroxybenzotriazole hydrate (HOBT) in a suitable solventsuch as DMF. Removal of the protecting group P to provide V may beachieved by standard procedures known in the art. For example, if P is abenzyl group, it may be removed by treatment of IV with hydrogen gas inthe presence of a catalyst such as palladium on carbon in a suitablesolvent such as EtOH. The resulting intermediate V may then be coupledwith the desired halo heterocycle VI (Z=halogen) bearing R⁶ in thepresence of a suitable base to provide I. Ar¹ and R⁶ may be furthermodified by standard synthetic methods known in the art to produceadditional compounds of formula (I). Several examples are described inthe Synthetic Examples section below.

[0140] In a modification of the above method, the order of coupling VIand Ar¹NH₂ with the central heterocycle may be reversed. This isillustrated in Scheme II.

[0141] As illustrated above, the ester VII (R=lower alkyl such as methylor ethyl, P=a protecting group) is deprotected as described above andthe resulting intermediate VIII is coupled, as described above toprovide ester IX. This is hydrolyzed using standard hydrolysisconditions and the resulting acid coupled with Ar¹NH₂ to provide I. Asabove, Ar¹ and R⁶ may be further modified by standard synthetic methodsknown in the art to produce additional compounds of formula (I). Severalexamples are described in the Synthetic Examples section below.

SYNTHETIC EXAMPLES

[0142] Example 1

Synthesis of1-methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

[0143]

[0144] For a similar procedure to form the indole core, see R. Albrechtet al. Eur. J. Med. Chem. Chim. Ther. 1985, 20, 59-60.

[0145] In a 1 L 3-neck round-bottom flask equipped with a condenser andmechanical stirrer were placed the 2-nitro-3-methylphenol (50.8 g, 331.5mmol), 500 mL anhydrous acetonitrile and potassium carbonate (57.3 g,414.3 mmol). The yellow solution became orange. While stirring, benzylbromide (39.4 mL, 331.5 mmol) was added slowly via syringe, then themixture was heated to gentle reflux overnight and allowed to cool. Anorange precipitates formed. The reaction was quenched with water andextracted with EtOAc three times. The combined organic extracts werewashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The desired benzyl ether was obtained as a yellow oil, 80.7 g(quantitative).

[0146] Potassium tert-Butoxide solution (1.0 M in THF, 100 mL, 100 mmol)was placed in a 1000 mL round-bottom flask under inert atmosphere. Ether(370 mL) was then added causing the solution to become murky. This wasfollowed by addition of diethyl oxalate (14.0 mL, 103.1 mmol). Thesolution became yellow. After stirring 10 min, the benzyl ether fromabove (24.3 g, 99.9 mmol) was added directly to the flask and themixture was left standing overnight. The reaction was heated to a gentlereflux for 18 h then left at room temperature overnight. An orangeprecipitate had formed. The precipitated product was filtered through aBuchner funnel and washed ether providing 29.1 g of the desiredcondensation product as the potassium salt.

[0147] In a 1 L 3-neck round-bottom flask equipped with a condenser andmechanical stirrer were placed the potassium salt from above (29.1 g,76.3 mmol) and 250 mL glacial acetic acid. Iron powder (25.6 g, 458.0mmol) was added and the reaction was stirred at 100° C. for 1 h and thenallowed to cool. EtOAc (800 mL) was added and the mixture was filteredthrough diatomaceous earth and left standing overnight. A saturatedaqueous solution of NaHCO₃ was added slowly to the filtrate. A lot ofbubbling was observed. The layers were separated and the organic phasewas washed with water and brine, dried (MgSO₄), filtered andconcentrated in vacuo. The resulting product was dried under high vacuumovernight. It was then decolorized with charcoal by heating in anEtOH/MeOH mixture, filtered and concentrated in vacuo, providing 7.5 gof the desired indole ester.

[0148] The indole ester (19.0 g, 64.3 mmol) was dissolved in 160 mLanhydrous DMF at room temperature and treated with sodium hydride (4.0g, 100 mmol), added portionwise. Once the mixture cooled back to roomtemperature, iodomethane (6.2 mL, 100 mmol) was added. Vigorous heatingwas again observed. One extra equivalent of iodomethane was added. Themixture was left stirring overnight and was then partitioned betweenEtOAc and saturated aqueous ammonium chloride solution. The organicphase was washed with water twice, then brine, dried (MgSO₄), filteredand concentrated in vacuo leaving a brown oil. The product was purifiedby column chromatography on SiO₂ using 10, 20% EtOAc in hexanes aseluent. The 1-methyl indole ester (17.2 g, mixture of methyl and ethylesters) was isolated as a pale yellow solid.

[0149] The above ester (4.01 g, 13.0 mmol) was placed in 100 mL THF andtreated with LiOH hydrate (1.1 g, 26.0 mmol) dissolved in 15 mL water.The resulting slightly murky solution was left stirring vigorously atroom temperature for 3 days. It was then acidified with dilute aqueousHCl to pH˜1 and extracted with EtOAc twice. The extracts were washedwith brine twice and dried (MgSO₄), filtered and concentrated in vacuo.The resulting carboxylic acid (3.75 g, quantitative) was obtained as awhite solid.

[0150] The carboxylic acid (0.93 g, 3.31 mmol) in 10 mL anhydrous DMF atroom temperature under N₂ was treated withO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (1.71 g, 4.50 mmol), triethylamine (1.75 mL,12.57 mmol) and catalytic 1-hydroxy-7-azabenzotriazole (HOAt) (231 mg,1.70 mmol). After 10 min at room temperature the aniline hydrochloridesalt was added in one portion. The mixture was left to stir at roomtemperature overnight, then diluted with EtOAc, washed with water,dilute aqueous HCl, water again and finally brine. The solution was thendried (MgSO₄), filtered and concentrated in vacuo leaving a brown foam.The product was purified by SiO₂ column chromatography using EtOAc inhexane eluent mixtures providing the desired amide (1.05 g) as a whitesolid.

[0151] The above amide (1.00 g, 1.87 mmol) was dispersed in 25 mLabsolute EtOH. A slurry of 20% Pd(OH)₂ in EtOH was added by pipet (230mg). The mixture was stirred under an atmosphere of H₂. After 3 h thereaction was filtered through diatomaceous earth and concentrated invacuo, providing the debenzylated hydroxy indole amide (843 mg) as alight yellow solid.

[0152] The hydroxy indole amide (824 mg, 1.85 mmol) was dissolved in 10mL anhydrous acetonitrile. DBU (0.277 mL, 1.85 mmol) was added, followedby 2,4-dichloropyrimidine (276 mg, 1.85 mmol) and the reaction was leftstirring at room temperature for 1.5 h, then concentrated in vacuo. Theresidue was loaded on a SiO₂ column and purified, eluting with EtOAc inhexanes mixtures. The 2-chloropyrimidinyl ether (367 mg) was isolated asa white solid.

[0153] The 2-chloropyrimidinyl ether (104 mg, 0.186 mmol) was placed in1.5 mL anhydrous THF followed by 1-methylpiperazine (0.042 mL, 0.375mmol). The mixture was stirred in a sealed tube overnight at 75° C. Itwas then allowed to cool, then water was added and the mixture wasextracted with CH₂Cl₂ twice. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo, leaving an orange foam.This was dissolved in acetonitrile and heated until product precipitatedas an off-white solid that was collected by filtration through vacuumBuchner funnel and air dried. The title compound (80 mg) was obtained asan off-white solid.

Example 2 Synthesis of1-methyl-7-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

[0154]

[0155] The 2-chloropyrimidinyl ether intermediate (75 mg, 0.13 mmol)(see Example 1) was dissolved in 1.0 mL anhydrous THF, treated withtriethylamine (21 uL, 0.15 mmol) and 4-aminoethylmorpholine (18 uL, 0.13mmol). The solution was placed in a sealed tube and stirred in a 75° C.bath overnight. The reaction was then allowed to cool, partitionedbetween water and EtOAc, and the aqueous phase was extracted with moreEtOAc. The combined organic extracts were dried (MgSO₄), filtered, andconcentrated in vacuo leaving a yellow foam (92 mg). The product waspurified by SiO₂ column chromatography, using MeOH in dichloromethaneeluent. The resulting white foam was suspended in a little acetonitrileand heated to boiling until it dissolved. Upon cooling slowly cool toroom temperature, crystals of the desired amino-pyriminyl etherprecipitated out. These were collected by vacuum filtration with aBuchner finnel providing the title compound (57 mg), mp: 201-202° C.

Example 3 Synthesis of1-methyl-7-(2-morpholin-4-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

[0156]

[0157] The 2-chloropyrimidinyl ether intermediate (500 mg, 0.896 mmol)(see Example 1), vinyltributyltin (600 mg, 1.89 mmol), BHT (20 mg), and(PPh₃)₄Pd (50 mg, 0.045 mmol) were suspended in degassed toluene (10 mL)under argon and heated to 115° C. for 3 h. The reaction mixture wascooled, diluted with EtOAc (100 mL), washed with brine (10 mL), anddried over MgSO₄. Silica gel chromatography (gradient elution, 0% to 80%EtOAc in hexanes) provided the desired 2-vinylpyrimidinyl etherintermediate (302 mg, 61%) as a pale yellow solid.

[0158] The 2-vinylpyrimidinyl ether (152 mg, 0.277 mmol) was dissolvedin 8:1 acetone/water (10 mL). N-methylmorpholine-N-oxide (150 mg, 1.28mmol) and OSO₄ (50 μL of a 2.5 wt % solution in tert-butanol) were addedand the reaction was stirred at room temperature for 6 h. Sodium sulfite(250 mg) in water (20 mL) was added, and the solution was stirred atroom temperature for 15 min. The reaction mixture was extracted withdichloromethane (4×20 mL), and the combined organic extracts dried overNa₂SO₄ and concentrated. Recrystallization from dichloromethane/hexanesprovided the desired diol as a white powder (105 mg, 65%).

[0159] To a vigorously stirred suspension of silica gel (20 g ) indichloromethane (80 mL) was added a solution of sodium periodate (1.40g, 6.55 mmol) in water (10 mL) over two min. A solution of the diol(1.25 g, 2.14 mmol) in dichloromethane (10 mL) was then added in oneportion. After stirring at room temperature for 2 h, the mixture wasfiltered through a sintered glass frit with copious dichloromethane andEtOAc washings. The filtrate was dried over MgSO₄ and concentrated toprovide the desired aldehyde as a pale brown solid (1.08 g, 91%).

[0160] To a vigorously stirred solution of the aldehyde (52 mg, 0.094mmol), morpholine (200 μL), and acetic acid (150 μL) in1,2-dichloroethane (4 mL) was added sodium triacetoxyborohydride (100mg, 0.472 mmol). The resulting mixture was stirred at room temperaturefor 16 h. Saturated NaHCO₃ (1 mL) and brine (3 mL) were added and themixture was stirred for a further 10 min. Extraction withdichloromethane (3×20 mL) was followed by drying (MgSO₄), and removal ofthe solvent. Silica gel chromatography (gradient elution, 0 to 10% MeOHin dichloromethane, 0.3% NH₄OH) provided the title compound as anoff-white solid (40 mg, 68%).

Example 4 Synthesis of1-methyl-7-(pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

[0161]

[0162] The 2-chloropyrimidinyl ether intermediate (100 mg, 0.179 mmol)(see Example 1) was dissolved in a mixture of EtOH and CH₃CN (4:1, total10 mL, using heat gun to complete dissolution). The reaction was cooledto room temperature under N₂ then 10% palladium-on-carbon (35 mg) wasadded and the reaction vessel was purged with H₂ several times. Thereaction was stirred under H₂ (balloon). After stirring at roomtemperature for 4 h the reaction was filtered through diatomaceous earthand washed with CH₃CN. The solvents were removed in vacuo and theresidue dissolved in CH₂Cl₂ (not totally soluble) and purified by flashcolumn chromatography using EtOAc/hexanes as eluent mixtures, providing24 mg of the title compound.

Example 5 Synthesis of1-methyl-7-[2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

[0163]

[0164] The chloropyrimidinyl ether intermediate (see Example 1) (0.250g, 0.448 mmol) was dissolved in 5 mL CH₃CN in a 15 mL pressure tube. Ina single portion, a mixture of 4-(2-hydroxyethyl)morpholine (0.080 g,0.61 mmol) and DBU (0.11 g, 0.73 mmol) were added. The tube was washeddown with 5 mL CH₃CN, sealed, and heated to about 95° C. (oil bath temp)for 48 h. The oil bath was raised to 110° C. and heating continuedanother 18 h. The reaction was allowed to cool, stripped to an amber oiland partitioned between EtOAc and water. The organic phase was washedwith water, then brine, and dried over MgSO₄. The organic layer wasstripped again to approximately 300 mg of amber oil, absorbed ontosilica, and the product purified by flash column chromatography on SiO₂using 5-25% iPrOH in CH₂Cl₂ as eluents. Concentration of theproduct-rich fractions afforded 40 mg of the title compound.

Example 6 Synthesis of1-methyl-7-(2-methylcarbamoyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

[0165]

[0166] To a solution of the indole ester intermediate (see Example 1)(1.26 g, ˜4 mmol) in 25 mL, of EtOAc was added 10% Pd/C (250 mg). Thereaction vessel was purged with N₂. and 1,4-cyclohexadiene (1.92 mL,20.5 mmol) was added via syringe. The reaction mixture was heated toreflux for 5 h, then cooled to room temperature, filtered through a padof diatomaceous earth, and rinsed with EtOAc. The resulting solution wasevaporated to afford a pink solid which was purified by columnchromatography on SiO₂ (4:1 hexanes-EtOAc) to give 740 mg of the desired7-hydroxyindole intermediate.

[0167] To a solution of the 7-hydroxyindole (200 mg, 0.912 mmol) in 2 mLof dry THF was added NaH (40 mg of a 60% dispersion in mineral oil)resulting in a deep blue solution.

[0168] A solution of 4chloropyridine-2carboxylic acid t-butyl ester (256mg, 1.20 mmol) in 1 mL of DMF was added and the mixture was heated to120° C. under N₂ for 5 h. After cooling down, the reaction mixture wasdiluted with EtOAc, washed with water, brine, dried (Na₂SO₄) andfiltered. After removal of solvents, the residue was purified by columnchromatography on silica gel, eluting with 4:1 hexanes-EtOAc to give 50mg of the desired diester.

[0169] The above diester (170 mg, 0.43 mmol) was dissolved in 4 mLCH₂Cl₂, and 1,3-dimethoxybenzene and 1 mL of TFA were added and thereaction was stirred overnight. After removal of the solvents, water wasadded to the oily residue and the pH adjusted to 3-4 with NaHCO₃ andextracted with CH₂Cl₂. The extracts were washed with brine, dried(Na₂SO₄) and filtered. After removal of the solvents, the desiredcarboxylic acid was used in next step without further purification.

[0170] To a solution of the carboxylic acid (160 mg, 0.47 mmol) in 2 mLof DMF were added Hunig's base (200 uL, 1.15 mmol), HATU (226 mg, 0.576mmol), HOAt (8.2 mg, 0.06 mmol) and MeNH₂ (0.5 mL of a 2.0 M solution inTHF, 1 mmol) successively. The reaction was stirred overnight, thendiluted with EtOAc, washed with water, brine, and dried (Na2SO₄). Afterremoval of the solvent, the residue was purified by columnchromatography on SiO₂ (3:1 hexanes-EtOAc) to give 120 mg of the desiredmethylamide.

[0171] The above methylamide (110 mg, 0.311 mmol) was dissolved in 3 mLof THF and LiOH (26 mg, 0.62 mmol) was added as a solution in 1 mLwater. The mixture was stirred at room temperature overnight. Thereaction mixture was partitioned between CH₂Cl₂ and water, and the waterwas separated and adjusted to pH to 3-4 with HCl and extracted againwith CH₂Cl₂. The combined organic layers were washed with brine, dried(Na₂SO₄) and filtered. After removal of the solvent, the carboxylic acidwas obtained as a solid which was used in next step without anypurification.

[0172] To a suspension of the above carboxylic acid (60 mg, 0.185 mmol)in 1.5 mL of DMF was added Hunig's base (87 uL, 0.50 mmol). After 5 min,HATU (90.2 mg, 0.23 mmol) and HOAt (5.0 mg, 0.037 mmol) were addedfollowed by N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide(51.8 mg, 0.190 mmol). The mixture was stirred overnight and was thendiluted with EtOAc, washed with water, brine, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purifed twice by flashcolumn chromatography (3-5% MeOH in CH₂Cl₂) to give 85 mg of the desiredproduct with some impurities. Final purification by reverse-phase HPLC(water:acetonitrile) gave 45 mg of the title compound.

Example 7 Synthesis of1-methyl-7-(2-morpholin-4-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

[0173]

[0174] A mixture of the 2-methyl-4-chloropyridine (1.00 g, 7.84 mmol),NBS (1.42 g, 8.00 mmol) and benzoyl peroxide (˜10 mg) in 10 mL of CCl₄was heated at reflux for 5 h. After cooling down, the reaction mixturewas filtered and filtrate was concentrated to give the crude productsmixture, which was dissolved in DMF and treated with morpholine (1.00mL) and K₂CO₃ (1 g). The mixture was stirred overnight. The mixture wasthen diluted with EtOAc, washed with water, brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography on SiO₂ to give 400 mg of the desired2-morpholinomethyl-4-chloropyridine.

[0175] To a solution of the 7-hydroxyindole ester (see Example 6) (473.6mg, 2.16 mmol) in 10 mL of dry DMF was added NaH (86.4 mg of a 60%dispersion in mineral oil, 2.16 mmol), resulting in a deep bluesolution. A solution of the 4-chloropyridine intermediate from above(380 mg, 1.79 mmol) in 3 mL of DMF was added and the mixture was heatedto 140° C. in a sealed tube for 4.5 h. After cooling down, the reactionmixture was diluted with EtOAc, washed with water, brine, dried (Na₂SO₄)and filtered. After removal of solvent, the residue was purified bycolumn chromatography on silica gel eluting with 1-4% MeOH in CH₂Cl₂ togive 240 mg of a mixture of unreacted chloropyridine and the desiredether intermediate, which was used in next step without furtherpurification.

[0176] The mixture of the above ether and unreacted chloropyridine wasdissolved in 3 mL of THF and was treated with 1 mL of aqueous LiOH (60mg) solution. The reaction mixture was stirred overnight and then wasconcentrated in vacuo. The residue was diluted with 1 M NaOH andextracted with ether to remove unreacted 7-hydroxyindole ester andchloropyridine. The aqueous layer was then acidified with 2 M HCl to pH4-5 and extracted with CH₂Cl₂ 6 times. The combined organic extractswere dried (Na₂SO₄), filtered and concentrated to give 68 mg of thedesired indole acid.

[0177] To a solution of the indole acid (65.0 mg, 0.177 mmol) in 2 mL ofDMF was added Hunig's base (87 uL, 0.50 mmol). After 5 min, HATU (90.2mg, 0.23 mmol) and HOAt (5 mg, 0.037 mmol) were added, and thenN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (49 mg,0.180 mmol). The mixture was stirred overnight. The reaction mixture wasdiluted with EtOAc, washed with water, brine, dried (Na₂SO₄), filteredand concentrated in vacuo. The crude product was purified by preparativeTLC (10% MeOH in DCM) to give 35 mg of product, which was purified byreverse-phase HPLC to give 20 mg of the title compound.

Example 8 Synthesis of7-(2-dimethylaminomethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

[0178]

[0179] A mixture of 4-chloropyridine-2-carboxylic acid (2.00 g, 12.69mmol), methyl iodide (1.25 mL, 20.0 mmol) and DBU (3.34 mL, 22.0 mmol)in 20 mL of dry acetonitrile was stirred over 2 days. The reactionmixture was diluted with ether, washed with water, brine, dried overNa₂SO₄ and concentrated. The residue was purified by chromatography onsilica gel to give 1.6 g of the desired methyl ester.

[0180] To a solution of DIBAL in toluene (1 M, 12.3 mL, 12.3 mmol) andTHF (1:1) in an ice-salt bath, was added a solution of the above ester(700 mg, 4.10 mmol) in 10 mL of THF. After addition, the reactionmixture was allowed to warm up to room temperature and stir for 3 h. Themixture was then poured into crushed ice with 5 mL of 4M NaOH, extractedwith EtOAc, dried over Na₂SO₄ and concentrated in vacuo to give 450 mgof the desired alcohol, which was used in next step withoutpurification.

[0181] To a solution of the above alcohol (430 mg, 3.0 mmol) in DMF (10mL) was added NaH (144 mg of a 60% dispersion in mineral oil, 3.60 mmol)and the mixture was then cooled in an ice bath. Benzyl bromide (437 uL,3.60 mmol) was then added and the mixture was stirred at roomtemperature for 3 h. After normal aqueous work-up and short columnchromatographic purification, 600 mg of desired benzyl ether wasobtained.

[0182] A Schlenk tube was charged with Pd(OAc)₂ (16 mg, 0.07 mmol),K₃PO₄ (525 mg, 2.40 mmol), di-t-butylbiphenylphosphine (42 mg, 0.14mmol) and the 7-hydroxyindole ester (see Example 6) (307 mg, 1.4 mmol),and capped with a septum and purged with argon. A solution of the benzylether from above (270 mg, 1.16 mmol) in 3 mL of toluene was then addedvia syringe. The mixture was heated at 100° C. with stirring under argonfor 6 h. The reaction mixture was filtered through a layer ofdiatomaceous earth and the solid residue was rinsed with CH₂Cl₂. Thecombined filtrate was concentrated. The crude product was purified bycolumn chromatography to give 61% yield of the desire indole ether.

[0183] To a solution of the indole ether (400 mg, 0.96 mmol) in 8 mL THFwas added a solution of LiOH (120 mg, 2.86 mmol) in 2.5 mL of H₂O. Themixture was stirred overnight, then was diluted with water, acidifiedwith 2 N HCl to pH 4-5, and extracted with CH₂Cl₂. The combined extractswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo togive 360 mg of desired carboxylic acid, which was pure enough for thenext step without purification.

[0184] To a solution of the indole carboxylic acid (360 mg, 0.93 mmol)in 4 mL of DMF was added Hunig's base (418 uL, 2.4 mmol). After 5 min,HATU (439 mg, 1.12 mmol) and HOAt (12 mg, 0.09 mmol) were added and thenN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (253 mg,0.93 mmol). The mixture was stirred overnight. The reaction mixture wasdiluted with EtOAc, washed with water, brine, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography (1:2 hexanes-EtOAc) to give 390 mg of the desired amide.

[0185] To a solution of the amide (390 mg, 0.61 mmol) in 4 mL of HOAcwas added 2 mL of concentrated HCl and the mixture was heated at 100° C.for 3 h. After cooling down, the reaction mixture was poured intocrushed ice, adjusted to pH to 5-6, extracted with EtOAc, washed withsaturated aqueousd NaHCO₃, brine, and dried over Na₂SO₄. After removalof the solvent, the residue was purified by column chromatography (3-5%MeOH in CH₂Cl₂) to give 180 mg of the desired debenzylatedpyridine-methanol.

[0186] To a solution of the pyridine-methanol (63 mg, 0.11 mmol) andCBr₄ (76 mg, 0.23 mmol) in 2 mL of CH₂Cl₂ was added Ph₃P (36 mg, 0.14mmol) at 0° C. and the mixture was stirred at 0° C. for 1 h. Thereaction mixture was concentrated in vacuo and the resulting yellow foamwas dissolved in 2 mL DMF, to which was added 1 mL of 2 M Me₂NH in THFand solid K₂CO₃. The mixture was stirred at room temperature for 3 h.The reaction mixture was diluted with EtOAc, washed with water, brine,dried (Na₂SO₄) and concentrated in vacuo. The crude product was purifiedby column chromatography to give 15 mg of the title compound.

Example 9 Synthesis of1-methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-3-methylcarbamoyl-phenyl)-amide

[0187]

[0188] To a solution of 7-hydroxyindole ester (see Example 6) (2.10 g,10 mmol) in DMSO (25 mL) was added t-BuOK solution in THF (1.0 M, 10 mL,10 mmol) at room temperature. The reaction color changed from red togreen. 2,4-Dichloropyrimidine (1.50 g, 10 mmol) was then added. Thereaction mixture was heated to 70° C. for 3 h. The reaction was cooled,diluted with H₂O and extracted with EtOAc. The combined organics werewashed with water and brine, dried over MgSO₄, filtered and concentratedto give a crude solid. The solid was triturated with 30% EtOAc/hexanesand filtered to give 1.4 g of the desired ether. The filtrate wasconcentrated down and purified by column chromatography on SiO₂ (15%-40%EtOAc/hexanes eluent) to give an additional 1.2 g of the etherintermediate as a white solid, for a combined yield of 2.6 g (78%).

[0189] To a solution of the above chloro-pyrimidinyl ether (1.00 g, 3.01mmol) in 15 mL anhydrous THF in a sealed tube was added 6.0 eq of MeNH₂solution in THF. The reaction was heated at 70° C. overnight. It wasthen cooled down to room temperature, diluted with water and extractedwith EtOAc. The organics were washed with brine, dried, filtered andconcentrated to give a foam, which was purified by flash columnchromatography on SiO₂ (20%-50% EtOAc/hexanes eluent) to give 812 mg ofdesired methylamino-pyrimidine intermediate.

[0190] To a solution of the above intermediate (812 mg, 2.49 mmol) inMeOH/THF (15 mL/15 mL) was added LiOH as an aqueous solution (313 mg in2 mL of H₂O). The reaction color changed to light green. The reactionwas sitrred at room temperature for 6 h, then concentrated in vacuo.Water was added, the mixture was washed with Et₂O and the organic layerwas discarded. The aqueous phase was acidified to pH 3-4 with 3N HCl andextracted with EtOAc. The combined organic extracts were dried, filtered(MgSO₄) and concentrated down to give 580 mg of the indole carboxylicacid as a pale pink solid.

[0191] To a solution of the above indole carboxylic acid (122 mg, 0.41mmol) in DMF were added HATU (141 mg, 0.37 mmol), TEA (104 uL, 0.74mmol) and HOAt (25 mg, 0.19 mmol). After 10 min, the anilineintermediate (88 mg, 0.37 mmol) was added in one portion. The mixturewas stirred at room temperature for 8 h. The reaction was then dilutedwith EtOAc and washed with water. Most starting aniline was removed bywashing with 0.5 N aqueous HCl. The resulting organics were dried(MgSO₄), filtered and concentrated to give an oil which was purified bycolumn chromatography on SiO₂ (3%-10% MeOH/CH₂Cl₂ eluents) followed bypreparative TLC to give 110 mg of the title compound.

Example 10 Synthesis of1-methyl-7-[2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

[0192]

[0193] To a suspension in EtOH (3 mL) of the olefin illustrated above(200 mg, 0.364 mmol) was added morpholine (65 μL, 0.75 mmol) and aceticacid (35 μL, 0.61 mmol). The mixture was heated to 80° C. under nitrogenfor 4 h, after which time a homogeneous solution was obtained. Thereaction was diluted with dichloromethane (10 mL) and stirred overanhydrous K₂CO₃ for 30 min. The solution was then filtered andconcentrated. Trituration of the residue with Et₂O provided the product(221 mg, 95%) as a tan powder.

Example 11 Synthesis of1-methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

[0194]

[0195] To a suspension of the indole carboxylic acid (2.10 g, 7.47 mmol)in dichloromethane (40 mL) was added oxalyl chloride (6.0 mL of a 2.0 Msolution in dichloromethane, 12 mmol) and DMF (10 μL) under anatmosphere of dry N₂. After stirring at ambient temperature for 1.5 h,the resulting yellow solution was concentrated in vacuo to provide thecrude acid chloride as a yellow powder. This material was dissolved inTHF (50 mL), and to this solution was addedN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (2.13 g,7.50 mmol), pyridine (971 μL, 12.0 mmol) and DMAP (50 mg). The reactionwas stirred at ambient temperature for 4 days, then taken up indichloromethane (300 mL), washed with saturated NaHCO₃ (40 mL), andconcentrated in vacuo. The resulting solids were triturated with etherto provide the product (2.94 g, 72%) as an analytically pure whitepowder.

[0196] O-de-benzylation and further transformation to the title compoundwere performed as previously described (Example 1) to afford the titlecompound.

Example 12 Synthesis ofN-[3-amino-2-methoxy-5-(1-methylcyclopropyl)-phenyl]-methanesulfonamide

[0197]

[0198] To a solution of 4-hydroxyacetophenone (10.0 g, 73.5 mmol) in DMF(74 mL) was added imidazole (12.0 g, 176.3 mmol) andtert-butyldimethylsilyl chloride (13.3 g, 88.1 mmol). The colorlesssolution was stirred for 0.75 h at room temperature then quenched withsaturated aqueous NaHCO₃. The aqueous phase was extracted with hexanesand the combined organic layers were washed with saturated aqueousNaHCO₃. The organic layers were dried over sodium sulfate, filtered, andconcentrated to provide the silyl ether (18.0 g, 98%) as a white solidwhich was utilized without further purification.

[0199] Methyl(triphenylphosphonium) bromide (17.1 g, 48.0 mmol) wassuspended in THF (96 mL) and cooled to 0° C. n-Butyllithium (2.5 M inhexane, 19.2 mL, 48.0 mmol) was added dropwise to the mixture. The redsolution was stirred at room temperature for 0.5 h. The acetophenonesilyl ether (10.0 g, 40.0 mmol) from above was added. The solutionturned bright yellow and a white precipitate formed. The mixture wasstirred for 1 h at room temperature and then the solution was quenchedwith saturated aqueous NaHCO₃. The aqueous phase was extracted withdiethyl ether and the combined organic layers were washed with saturatedaqueous NaHCO₃. The organic layers were dried over sodium sulfate,filtered and concentrated. The resulting mixture was eluted through aplug of silica gel (hexanes) and the filtrate was concentrated toprovide the styrene (8.36 g, 84%) as a colorless oil.

[0200] Diethylzinc (1.0 M in hexanes, 69 mL, 69 mmol) was added to asolution of the above styrene intermediate (6.85 g, 27.6 mmol) indichloroethane at 0° C. Diiodomethane (11.2 mL, 138 mmol) was then addeddropwise to the solution and the resulting mixture was stirred at 0° C.for 0.5 h and allowed to warm to room temperature for 2 h. The opaquemixture was quenched with saturated aqueous NH₄Cl. The aqueous phase wasextracted with methylene chloride and the combined organic layers werewashed with saturated aqueous NaHCO₃. The organic layers were dried oversodium sulfate, filtered through diatomaceous earth, and concentrated.The crude residue was dissolved in THF (50 mL) and TBAF (1.0 M in THF,28 mL, 28 mmol) was added at room temperature. The solution was stirredfor 2 h and then quenched with aqueous 1.0 M HCl. The aqueous phase wasextracted with EtOAc and the combined organic layers were washed withsaturated aqueous NaHCO₃. The organic layers were dried over sodiumsulfate, filtered and concentrated. Purification by silica-gelchromatography (1% 2-propanol/12% EtOAc in hexanes) provided the phenol(2.77 g, 68%) as a white solid: (NO)18-crown-6•H(NO₃)₂ ¹(18.0 g, 43.0mmol) was added to a solution of phenol (2.77 g, 18.7 mmol) in EtOAc.The reaction mixture was heated to reflux for 5 min and then cooled toroom temperature. The mixture was poured onto aqueous 1.0 M HCl. Theaqueous phase was extracted with diethyl ether. The combined organiclayers were dried over sodium sulfate, filtered and concentrated. Theresidue was dissolved in acetonitrile/MeOH (9:1, 62 mL), cooled to 0° C.and N,N-diisopropylethylamine (13 mL, 74.8 mmol) was added slowly. Thedeep red solution was warmed to room temperature andtrimethylsilyldiazomethane (2.0 M in hexane, 18.7 mL, 37.4 mmol) wasadded slowly to control nitrogen evolution. After stirring at roomtemperature for 0.5 h, the mixture was concentrated and partitionedbetween methylene chloride and saturated aqueous NH₄Cl. The aqueouslayer was extracted with methylene chloride and the combined extractswere dried over sodium sulfate, filtered and concentrated. Purificationby silica-gel chromatography (6% EtOAc in hexanes) provided thedinitroanisole (2.21 g, 47%) as a red oil.

[0201] Tin(II)chloride dihydrate (11.9 g, 52.6 mmol) was added to asolution of the above dinitroanisole (2.21 g, 8.76 mmol) in EtOAc (30mL). The mixture was heated to reflux for 0.25 h upon which the solutionbecame red in color. The solution was cooled to room temperature andpoured onto aqueous 2.0 M NaOH. The aqueous phase was extracted withEtOAc and the combined organic layers were washed with saturated aqueousNaHCO₃. The organic layers were dried over sodium sulfate, elutedthrough a plug of silica gel (1% ammonium hydroxide in methylenechloride), and the filtrate was concentrated. The residue was dissolvedin diethyl ether and extracted (3×) with 1.0 M HCl. The pH of thecombined aqueous layers was adjusted to pH=12 with 2.0M NaOH andextracted with methylene chloride. The combined organic layers weredried over sodium sulfate, filtered and concentrated to providediaminoanisole (860 mg, 52%) as a red oil.

[0202] Triethylamine (521 μL, 3.74 mmol) was added to a solution of theabove diaminoanisole (718 mg, 3.74 mmol) in methylene chloride at −10°C. Methanesulfonyl chloride (290 μL, 3.74 mmol) was then added dropwiseover a 10 min period and the resulting solution was allowed to slowlywarm to room temperature over 2 h. The mixture was quenched withsaturated aqueous NaHCO₃ and the aqueous layer was extracted withmethylene chloride. The combined organic layers were dried over sodiumsulfate, filtered and concentrated. Purification by silica gelchromatography (1% ammonium hydroxide/35% EtOAc in hexanes to 1%ammonium hydroxide/50% EtOAc in hexanes) provided a red solid which wastriturated with a diethyl ether/hexanes (1:1) to yield the titlecompound (510 mg, 51%) as a pale brown solid, mp 144-146° C.

[0203] This intermediate can then be coupled to the indole core andreacted further by the procedures described in the examples above, toform desired analogous indole amides.

[0204] For example, the product of Example 12 was used to prepare thefollowing compound:

Example 13 Synthesis of 7-mercapto-1-methyl-1H-indole-2-carboxylic acidethyl ester

[0205]

[0206] 7-Hydroxy-1-methylindole-2-carboxylic acid ethyl ester (1.06 g;0.005 mol) was dissolved in 8 mL DMF in a 3-neck round bottom flaskunder nitrogen purge. Diazabicyclo[2.2.2.]octane (DABCO) (1.12 g, 0.010mol) and Me₂NC(═S)Cl (1.236 g, 0.010 mol) were added sequentially, eachin a single portion. The mixture was left stirring at room temperatureovernight. A suspension formed. The reaction mixture was poured ontowater and extracted 3× with EtOAc. The combined organic layers werewashed 3× with water, then brine, then dried over MgSO₄, concentrated toa semi-solid, ca 1.6 g.

[0207] The above residue was taken up in hot i-PrOH (about 30 mL) andtreated with charcoal. The solution was cooled overnight in a freezer,then the resulting beige solid was filtered off and washed with coldi-PrOH, then petroleum ether providing the desired thiocarbamate (0.92g).

[0208] The above thiocarbamate (31 mg; 0.0001 mol) was added into apressure tube, along with Me₂NPh (0.63 mL; 0.005 mol) and a magneticstir bar. The tube was heated in a microwave oven to 250° C. for 10 min.The reaction mixture was then poured onto 4 N aqueous HCl and the gummyprecipitate was extracted with EtOAc. The solution was allowed toevaporate providing the desired isomerized intermediate.

[0209] The resulting intermediate can be hydrolyzed to form the desiredthiol, which can then be further reacted by the methods described abovefor the analogous 7-hydroxyindole intermediate to form the desiredthioether derivatives.

[0210] For example, the following compound may be prepared from theabove thiol using the methods described in the above examples:

Example 14 Synthesis of 7-hydroxy-benzo[b]thiophene-2-carboxylic acidmethyl ester

[0211]

[0212] To a 150 mL heating flask was added 1 g (5.52 mmol) of3-methoxy-2-nitro-benzaldehyde, 0.5 mL (5.7 mmol) of mercapto-aceticacid methyl ester, 1.8 g (13 mmol) of potassium carbonate and 50 mL ofanhydrous DMF. The opaque, gold solution was stirred overnight at 60° C.in a sealed tube. After 14 h the reaction was poured into 200 mL ofwater, stirred 2 h, and extracted with EtOAc to provide 1 g (81%) of thedesired intermediate, which was used without further purification.

[0213] Dissolved 1 g (4.5 mmol) of the above intermediate in about 50 mLCH₂Cl₂ in a 500 mL 3-neck round-bottom flask under nitrogen purge andcooled in an ice/acetone bath. Placed the BBr₃/CH₂Cl₂ solution (3 eq) inaddition funnel, and added dropwise at such a rate that the temperaturewas maintained <5° C. throughout. Allowed to warm to room temperatureand continued stirring overnight. The reaction was cooled back down inan ice/acetone bath and added 50 mL MeOH dropwise; initially veryslowly, since it was exothermic. After the addition of MeOH wascomplete, the reaction was allowed to warm to room temperature and thenconcentrated in vacuo to obtain the title compound (900 mg, 93%).

[0214] The 7-hydroxybenzothiophene intermediate can then be reactedfurther as described in Examples above for 7-hydroxyindole to producecompounds of formula I

Example 15 Synthesis of1-methyl-7-(2-pyrrolidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

[0215]

[0216] To a suspension of 4-chloropyridine-2-carboxylic acid (4.5 g,29.0 mmol) in methylene chloride (120 mL) was added oxalyl chloride (3.0mL, 1.2 eq) under Ar₂. The reaction was cooled to 0° C., added 500 uL ofDMF. A large amount of gas was generated in situ. The reaction wasstirred at room temperature for 1.5 h then concentrated. Dry MeOH (50mL) was added to the crude acyl chloride residue. The reaction wasstirred at room temperature for 0.5 h then quenched with NaHCO₃ (5%) toneutral, extracted with EtOAc, and washed with brine. The combinedorganics were dried over MgSO₄, filtered and concentrated in vacuo togive 5.0 g of crude solid which was triturated with 5% EtOAc/hexane togive the desired intermediate methyl ester as a light yellow solid (4.5g, 90%).

[0217] To a solution of the above methyl ester (2.5 g, 14.6 mmol) in 100mL of dry THF at −78° C. was added diisobutylaluminum hydride dropwise(1.0 M in THF, 29.1 mmol) and the reaction mixture was stirred at thattemperature under Ar₂ for 2 h. The reaction was quenched with MeOH at−78° C. and then sodium potassium tartrate solution (˜1.0 M, 180 mL) wasadded and the mixture was stirred and warmed up to room temperature over1 h. The slurry was diluted with EtOAc (60 mL) and the organic layer wasseparated and washed with brine and dried with sodium sulfate. Thesolvent was removed under mild vacuum at room temperature (volatilecompound) to give the desired aldehyde (1.87 g, 91%) which solidified asa light yellow crystal by standing at room temperature.

[0218] To a solution of the above aldehyde (1.6 g, 11.3 mmol) in 50 mLof MeOH (dry) was added TsOH.H₂O (363 mg, 0.17 eq) and (MeO)₃CH (5 mL).The reaction was heated up to reflux for 2 h then partitioned betweenEtOAc and water. The organic phase was then washed with NaHCO₃ solutionand brine. The combined organics were dried over MgSO₄, filtered andconcentrated in vacuo to give the desired4-chloro-2-dimethoxymethyl-pyridine as a light yellow oil (1.83 g, 86%).

[0219] A sealed tube was charged with Pd(OAc)₂ (57.47 mg, 0.06 eq),K₃PO₄ (1.904 g, 2.0 eq), di-tert butyl phosphine biphenyl (152.7 mg,0.12 eq) and 7-hydroxy-methylindole-2-carboxylic acid methyl ester(934.8 mg, 4.26 mmol) and toluene (20 mL), and capped with a septum. Thesystem was degased and charged with argon, repeated for a couple oftimes. Then a solution of the 4-chloro-2-dimethoxymethyl-pyridine (800mg, 4.26 mmol) from above in 4 mL of toluene was added via syringe. Themixture was heated at 100° C. with stirring under argon for 3 h. Thereaction was cooled to room temperature, and the reaction mixture wasfiltered through a pad of diatomaceous earth and rinsed with methylenechloride. The combined filtrates were concentrated in vacuo. The crudeproducts were purified by silica gel chromatography (30%-70% EtOAc/hex)to give the desired ether (790 mg, 50%) as a brown oil.

[0220] To a solution of the above ether (770 mg, 2.1 mmol) in THF/MeOH(25 mL/10 mL) was added LiOH.H₂O (218.1 mg, 2.50 eq) dissolved in 3 mLof water. The clear reaction solution was stirred at room temperaturefor 5 h, then concentrated in vacuo. The residual aqueous solution wasdiluted with water (15 mL), and extracted with ether. The organic layerwas disgarded. The aqueous layer was acidified to pH 5 with 1.4 N HCl(˜2.5 mL). A large amount of white precipitates were extracted with 200mL of EtOAc and washed with brine. The combined organics were dried overMgSO₄, filtered and concentrated in vacuo to give the desiredindole-2-carboxylic acid intermediate (644 mg, 90.5%) as a white foam.

[0221] To a soultion of the above carboxylic acid (651 mg, 1.9 mmol) inDMF (20 mL) were added HATU (723.2 mg, 1.0 eq) diisopropylethylamine(662.6 uL, 2.0 eq) and HOAt (129.4 mg, 0.5 eq). After 10 min,N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide was addedin one portion. After stirring at room temperature overnight, thereaction was worked up with EtOAc, washed with water and brine. Thecombined organics were dried over MgSO₄, filtered and concentrated invacuo to give an oil which was purified by silica gel Chromatography(50% EtOAc/hexanes) to give the desired amide (1.03 g, 91%) as a whitefoam.

[0222] To a solution of the above amide (1.08 g, 1.81 mmol) inacetonitrile and water (20 mL/20 mL) was added CBr₄ (905 mg, 2.0 eq).The reaction was refluxed (oil bath temperature: 80° C.) overnight. Thereaction was cooled to room temperature, adjusted to pH 7 with NaHCO₃solution, extracted with EtOAc until no desired product was left in theaqueous layer. The combined organics were dried over MgSO₄, filtered andconcentrated to give 1.5 g (>100%) of a light brown colored foam whichwas purified by silica gel chromatography (20%-70% EtOAc/hexanes) toprovide the desired aldehyde intermediate as a yellow foam.

[0223] To a solution of the above aldehyde (80 mg, 0.145 mmol) indichloroethane (10 mL) were added glacial HOAc (273 uL) and pyrrolidine(375 uL). The reaction was stirred at room temperature for 20 min. Thereaction solution became cloudy. Triacetoxyborohydride (245 mg) wasadded to the reaction mixture. The reaction was stirred at roomtemperature for 1 h, then NaHCO₃ (saturated solution) was added, themixture stirred for 10 min, then extracted with methylene chloride. Thecombined organics were washed with brine, dried over MgSO₄, filtered andconcentrated down to give 85 mg of foam which was >97% pure by HPLC and1 HNMR. The foam was further purified by silica gel chromatography(5%-8% MeOH/methylene chloride) to provide the title compound (75 mg,85%).

Example 16 Synthesis of1-methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-2-methoxy-phenyl)-amide

[0224]

[0225] To a solution of1-methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-[1,3]dioxolan-2-yl-2-methoxy-phenyl)-amide (0.20 g, 0.40mmol) in THF (3.00 mL) was added 2.0 N HCl (2 mL). The solution wasallowed to stir at room temperature and under an ambient atmosphere for17.5 h. The solution was diluted in EtOAc (20 mL) and transferred to aseparatory funnel. The.aqueous layer was separated and the organic layerwas washed with saturated NaHCO₃ solution (2×10 mL), water (1×10 mL),brine (1×10 mL), dried over MgSO₄, filtered-and the solvent wasevaporated to give the desired aldehyde as a yellow foam (0.16 g, 90%).

[0226] To a solution of the above aldehyde (0.04 g, 0.09 mmol) indichloroethane (2.00 mL) was added acetic acid (0.06 mL, 1.06 mmol)followed by the dropwise addition of N,N,N′-trimethylethylenediamine(0.28 mL, 2.18 mmol) at 0° C. The solution was allowed to warm to roomtemperature and was stirred for 30 min., followed by the batchwiseaddition of sodium triacetoxyborohydride (0.05 g, 0.22 mmol). Thereaction was allowed to stir for 17.5 h under an ambient atmosphere andat room temperature. The solution was diluted with EtOAc (10 mL) andquenched with 3% NH₄OH (1 mL). The biphasic system was transferred to aseparatory funnel and the aqueous layer was separated. The organic layerwas washed with 3% NH₄OH (2×2.0 mL), water (2×10 mL), brine (2×10 mL),dried over MgSO₄, filtered and the solvent was evaporated. The resultingresidue was dissolved in CH₂Cl₂ and flash chromatographed (7%MeOH/CH₂Cl₂, 0.5% NH₄OH) to give the crude product as a yellow oil. Thematerial was again flash chromatographed (8% MeOH/CH₂Cl₂, 0.5% NH₄OH) togive the title compound as a colorless foam (0.02 g, 41%).

Method of Use

[0227] In accordance with the invention, there are provided novelmethods of using the compounds of the formula (I). The compoundsdisclosed therein effectively block inflammatory cytokine productionfrom cells. The inhibition of cytokine production is an attractive meansfor preventing and treating a variety of cytokine mediated diseases orconditions associated with excess cytokine production, e.g., diseasesand pathological conditions involving inflammation. Thus, the compoundsare useful for the treatment of diseases and conditions as described inthe Background section, including the following conditions and diseases:

[0228] osteoarthritis, atherosclerosis, contact dermatitis, boneresorption diseases, reperfusion injury, asthma, multiple sclerosis,Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis,graft versus host disease, systemic lupus erythematosus andinsulin-dependent diabetes mellitus, rheumatoid arthritis, toxic shocksyndrome, Alzheimer's disease, diabetes, inflammatory bowel diseases,acute and chronic pain as well as symptoms of inflammation andcardiovascular disease, stroke, myocardial infarction, alone orfollowing thrombolytic therapy, thermal injury, adult respiratorydistress syndrome (ARDS), multiple organ injury secondary to trauma,acute glomerulonephritis, dermatoses with acute inflammatory components,acute purulent meningitis or other central nervous system disorders,syndromes associated with hemodialysis, leukopherisis, granulocytetransfusion associated syndromes, and necrotizing entrerocolitis,complications including restenosis following percutaneous transluminalcoronary angioplasty, traumatic arthritis, sepsis, chronic obstructivepulmonary disease and congestive heart failure. The compounds of theinvention may also be useful for anticoagulant or fibrinolytic therapy(and the diseases or conditions related to such therapy) as described inU.S. application Ser. No. 10/630,599 and PCT/US03/23841.

[0229] The compounds of the invention are also p38 MAP kinaseinhibitors. Methods for screening p38 MAP kinase inhibitors are known inthe art. As disclosed in the Background of the Invention, the compoundsof the invention will therefore be useful for treating oncologicaldiseases. These diseases include but are not limited to solid tumors,such as cancers of the breast, respiratory tract, brain, reproductiveorgans, digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukemias.

[0230] Examples of breast cancer include, but are not limited toinvasive ductal carcinoma, invasive lobular carcinoma, ductal carcinomain situ, and lobular carcinoma in situ.

[0231] Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma and mesothelioma.

[0232] Examples of brain cancers include, but are not limited to brainstem, optic and hypophtalmic glioma, cerebella and cerebral astrocytoma,medulloblastoma, ependymoma, as well as pituitary,neuroectodermal andpineal tumor.

[0233] Examples of peripheral nervous system tumors include, but are notlimited to neuroblastoma, ganglioneuroblastoma, and peripheral nervesheath tumors.

[0234] Examples of tumors of the endocrine and exocrine system include,but are not limited to thyroid carcinoma, adrenocortical carcinoma,pheochromocytoma, and carcinoid tumors.

[0235] Tumors of the male reproductive organs include, but are notlimited to prostate and testicular cancer.

[0236] Tumors of the female reproductive organs include, but are notlimited to endometrial, cervical, ovarian, vaginal, and vulvar cancer,as well as sarcoma of the uterus.

[0237] Tumors of the digestive tract include, but are not limited toanal, colon, colorectal, esophageal, gallblader, gastric, pancreatic,rectal, small-intestine, and salivary gland cancers.

[0238] Tumors of the urinary tract include, but are not limited tobladder, penile, kidney, renal pelvis, ureter, and urethral cancers.

[0239] Eye cancers include, but are not limited to intraocular melanomaand retinoblastoma.

[0240] Examples of liver cancers include, but are not limited tohepatocellular carcinoma (liver cell carcinomas with or withoutfibrolamellar variant), hepatoblastoma, cholangiocarcinoma (intrahepaticbile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

[0241] Skin cancers include, but are not limited to squamous cellcarcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skincancer, and non-melanoma skin cancer.

[0242] Head-and-neck cancers include, but are not limited tolaryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lipand oral cavity cancer.

[0243] Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, Hodgkins lymphoma, cutaneous T-cell lymphoma,and lymphoma of the central nervous system.

[0244] Sarcomas include, but are not limited to sarcoma of the softtissue, osteosarcoma, Ewings sarcoma, malignant fibrous histiocytoma,lymphosarcoma, angiosarcoma, and rhabdomyosarcoma. Leukemias include,but are not limited to acute myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia,and hairy cell leukemia.

[0245] Plasma cell dyscrasias include, but are not limited to multiplemyeloma, and Waldenstrom's macroglobulinemia.

[0246] These disorders have been well characterized in man, but alsoexist with a similar etiology in other mammals, and can be treated bypharmaceutical compositions of the present invention.

[0247] For therapeutic use, the compounds may be administered in anyconventional dosage form in any conventional manner. Routes ofadministration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

[0248] The compounds may be administered alone or in combination withadjuvants that enhance stability of the inhibitors, facilitateadministration of pharmaceutic compositions containing them in certainembodiments, provide increased dissolution or dispersion, increaseinhibitory activity, provide adjunct therapy, and the like, includingother active ingredients. Advantageously, such combination therapiesutilize lower dosages of the conventional therapeutics, thus avoidingpossible toxicity and adverse side effects incurred when those agentsare used as monotherapies. The above described compounds may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Reference is thisregard may be made to Cappola et al.: U.S. patent application Ser. No.09/902,822, PCT/US 01/21860 and U.S. application Ser. No. 10/214,782,each incorporated by reference herein in their entirety. Advantageously,the compounds may then be administered together in a single dosage form.In some embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 5%, but more preferablyat least about 20%, of a compound of formula (I) (w/w) or a combinationthereof. The optimum percentage (w/w) of a compound of the invention mayvary and is within the purview of those skilled in the art.Alternatively, the compounds may be administered separately (eitherserially or in parallel). Separate dosing allows for greater flexibilityin the dosing regime.

[0249] As mentioned above, dosage forms of the compounds describedherein include pharmaceutically acceptable carriers and adjuvants knownto those of ordinary skill in the art. These carriers and adjuvantsinclude, for example, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 1-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. Referencein this regard may also be made to U.S. application Ser. No. 10/313,667.As the skilled artisan will appreciate, lower or higher doses may berequired depending on particular factors. For instance, specific dosageand treatment regimens will depend on factors such as the patient'sgeneral health profile, the severity and course of the patient'sdisorder or disposition thereto, and the judgment of the treatingphysician.

Biological Assays

[0250] Inhibition of TNF Production in THP Cells

[0251] The inhibition of cytokine production can be observed bymeasuring inhibition of TNFα in lipopolysaccharide stimulated THP cells(for example, see W. Prichett et al., 1995, J. Inflammation, 45, 97).All cells and reagents were diluted in RPMI 1640 with phenol red andL-glutamine, supplemented with additional L-glutamine (total: 4 mM),penicillin and streptomycin (50 units/ml each) and fetal bovine serum(FBS, 3%) (GIBCO, all conc. final). Assay was performed under sterileconditions; only test compound preparation was nonsterile. Initial stocksolutions were made in DMSO followed by dilution into RPMI 1640 2-foldhigher than the desired final assay concentration. Confluent THP.1 cells(2×10⁶ cells/ml, final conc.; American Type Culture Company, Rockville,Md.) were added to 96 well polypropylene round bottomed culture plates(Costar 3790; sterile) containing 125 μl test compound (2 foldconcentrated) or DMSO vehicle (controls, blanks). DMSO concentration didnot exceed 0.2% final. Cell mixture was allowed to preincubate for 30min, 37° C., 5% CO₂ prior to stimulation with lipopolysaccharide (LPS; 1μg/ml final; Siga L-2630, from E.coli serotype 0111.B4; stored as 1mg/ml stock in endotoxin screened distilled H₂O at −80° C.). Blanks(unstimulated) received H₂O vehicle; final incubation volume was 250 μl.Overnight incubation (18-24 hr) proceeded as described above. Assay wasterminated by centrifuging plates 5 min, room temperature, 1600 rpm(400×g); supernatants were transferred to clean 96 well plates andstored −80° C. until analyzed for human TNFα by a commercially availableELISA kit (Biosource #KHC3015, Camarillo, Calif.). Data was analyzed bynon-linear regression (Hill equation) to generate a dose response curveusing SAS Software System (SAS institute, Inc., Cary, N.C.). Thecalculated IC₅₀ value is the concentration of the test compound thatcaused a 50% decrease in the maximal TNFα production.

[0252] Preferred compounds have an IC₅₀<1 uM in this assay.

[0253] Inhibition of Other Cytokines

[0254] By similar methods using peripheral blood monocytic cells,appropriate stimuli, and commercially available ELISA kits (or othermethod of detection such as radioimmunoassay), for a particularcytokine, inhibition of IL-1 beta, GM-CSF, IL-6 and IL-8 can bedemonstrated for preferred compounds (for example, see J. C. Lee et al.,1988, Int. J. Immunopharmacol., 10, 835).

[0255] All publications, patent publications and patent applicationscited in this application are incorporated herein by reference in theirentirety.

What is claimed is:
 1. A compound of the formula (I)

wherein: Ar¹ is an aromatic carbocycle substituted with one R¹, andwherein Ar¹ is independently substituted with two R² groups and whereinone R¹ and one R² on adjacent ring atoms optionally form a 5- or6-membered carbocyclic or heterocyclic ring; R¹ is halogen, NO₂, NH₂,J-N(R^(a))—(CH₂)_(m)—, N(J)₂-(CH₂)_(m)—, NH₂C(O)—, J-N(R^(a))—C(O)—,J-S(O)_(m)—N(R^(a))—, J-N(R^(a))—S(O)_(m)— or heterocycle-(CH₂)_(m)—wherein the heterocyclic group is optionally substituted by C₁₋₅ alkyl;Q is a N or CR^(p); Y is >CR^(p)R^(v), —CR^(p)═C(R^(v))—, —O—,—N(R^(x))— or >S(O)_(m); wherein R^(a), R^(p), R^(v), R^(x) and R^(y)are each independently hydrogen or C₁₋₅ alkyl; X is —CH₂—, —N(R^(a))—,—O— or —S—; W is N or CH; each m is independently 0, 1 or 2; J is chosenfrom C1-10 alkyl and carbocycle each optionally substituted by R^(b); R²is chosen from C1-6 alkyl, C3-7 cycloalkyl optionally substituted byC1-5 alkyl, C1-4 acyl, aroyl, C1-4 alkoxy, each being optionallypartially or fully halogenated, halogen, C1-6 alkoxycarbonyl,carbocyclesulfonyl and —SO₂—CF₃; each R³, R⁴ and R⁵ are independentlychosen from hydrogen, C1-6 alkyl and halogen; R⁶ is optionally attachedat a position ortho or meta to the N atom of the indicated ring, and ischosen from a bond, —O—, —O—(CH₂)₁₋₅—, >C(O), —NH—, —C(O)—NH—, —S—, C₁₋₅alkyl branched or unbranched, C₂₋₅ alkenyl, C₁₋₃ acyl, C₁₋₃ alkyl(OH),heterocycle selected from morpholinyl, piperazinyl, piperidinyl,pyrrolidinyl and tetrahydrofuranyl, heteroaryl selected from pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,thienyl, furyl, isoxazolyl, thiazolyl, oxazolyl and isothiazolyl or aryleach alkyl, alkenyl, acyl, heterocycle, heteroaryl and aryl areoptionally substituted by one to three hydroxy, oxo, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₅ alkoxycarbonyl, —NR₇R₈ or NR₇R₈—C(O)—; wherein each R₆ isfurther optionally covalently attached to groups chosen from: hydrogen,—NR₇R₈, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, hydroxy, C₁₋₃ alkoxy,phenoxy, benzyloxy, arylC₀₋₄ alkyl, heteroaryl C₀₋₄ alkyl andheterocycle C₀₋₄alkyl, each above-listed heterocycle, heteroaryl andaryl group is optionally substituted by one to three hydroxy, oxo, C₁₋₄alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, NR₇R₈—C(O)— or C₁₋₄ acyl; eachR₇ and R₈ are independently hydrogen, phenylC₀₋₃alkyl optionallysubtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino, or R₇ and R₈are C₁₋₂ acyl, benzoyl or C₁₋₅ branched or unbranched alkyl optionallysubstituted by C₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃ alkyl amino; andR^(b) is chosen from hydrogen, C1-5 alkyl, hydroxyC1-5 alkyl, C2-5alkenyl, C2-5 alkynyl, carbocycle, heterocycle, heteroaryl, C1-5 alkoxy,C1-5 alkylthio, amino, C1-5 alkylamino, C1-5 dialkylamino, C1-5 acyl,C1-5 alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, each of theaforementioned are optionally partially or fully halogenated, or R^(b)is chosen from C1-5 alkylsulphonylamino, hydroxy, oxo, halogen, nitroand nitrile; or the pharmaceutically acceptable salts, acids or isomersthereof.
 2. The compound according to claim 1 and wherein: Y is —O—,—S—, —NH—, —N(CH₂CH₃)— or —N(CH₃)—; X is —N(R^(a))—, or —O—; Q is CH; Jis chosen from C1-10 alkyl, aryl or C3-7 cycloalkyl each optionallysubstituted by R^(b); R₂ is independently chosen from C1-6 alkyl, C3-6cycloalkyl optionally substituted by C1-3 alkyl, acetyl, aroyl, C1-5alkoxy, each being optionally partially or fully halogenated, halogen,methoxycarbonyl, phenylsulfonyl and —SO₂—CF₃; each R³, R⁴ and R⁵ arehydrogen; R^(b) is chosen from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5alkynyl, C3-8 cycloalkylC0-2 alkyl, aryl, C1-5 alkoxy, C1-5 alkylthio,amino, C1-5 alkylamino, C1-5 dialkylamino, C1-5 acyl, C1-5alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, C1-5 sulphonylamino,hydroxy, halogen, trifluoromethyl, nitro, nitrile or R^(b) is chosenfrom; heterocycle chosen from pyrrolidinyl, pyrrolinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone,dioxalanyl, piperidinyl, piperazinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone,1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl, pentamethylenesulfide, pentamethylene sulfoxide, pentamethylene sulfone,tetramethylene sulfide, tetramethylene sulfoxide and tetramethylenesulfone and heteroaryl chosen from aziridinyl, thienyl, furanyl,isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl,pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl,indazolyl, triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl,pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl,oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl.
 3. The compoundaccording to claim 2 and wherein: Ar¹ is chosen from phenyl, naphthyl,tetrahydronaphthyl, indanyl and indenyl, each Ar¹ is optionallysubstituted with one R¹, and independently substituted with two R²groups; Y is —O—, —S— or —N(CH₃)—; R⁶ is present, and is chosen from abond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branched orunbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), heterocycle selected frommorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl andtetrahydrofuranyl, or aryl chosen from phenyl and naphthyl, each alkyl,alkenyl, heterocycle and aryl are optionally substituted by one to threehydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl amino, amino orC₁₋₅ alkoxycarbonyl; wherein each R₆ is further optionally covalentlyattached to groups chosen from: hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆cycloalkylC₀₋₂alkyl, hydroxy, C₁₋₃ alkoxy, phenoxy, benzyloxy,phenylC₀₋₄ alkyl, piperazinylC₀₋₄ alkyl, piperidinyl C₀₋₄alkyl,pyrrolidinylC₀₋₄ alkyl, morpholinylC₀₋₄ alkyl, tetrahydrofuranylC₀₋₄alkyl, triazolyl C₀₋₄alkyl, imidazolyl C₀₋₄alkyl and pyridinylC₀₋₄alkyl, each abovelisted heterocycle, heteroaryl and phenyl group isoptionally substituted by one to three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃alkoxy, C₁₋₅ alkoxycarbonyl, —NR₇R₈, NR₇R₈—C(O)— or C₁₋₄ acyl; each R₇and R₈ are independently hydrogen, phenylC₀₋₃alkyl optionally subtitutedby halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino, or R₇ and R₈ are C₁₋₂acyl, benzoyl or C₁₋₅ branched or unbranched alkyl optionallysubstituted by C₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃ alkyl amino. 4.The compound according to claim 3 and wherein: X is —O—; Y is —N(CH₃)—;J is C1-10 alkyl optionally substituted by R^(b); R₂ is independentlychosen from C1-6 alkyl, C3-6 cycloalkyl optionally substituted by C1-3alkyl and C1-5 alkoxy, each being optionally be partially or fullyhalogenated; R⁶ is chosen from a bond, —O—, —O—(CH₂)₁₋₅—, —NH—,—C(O)—NH—, C₁₋₅ alkyl branched or unbranched, C₂₋₅ alkenyl, C₁₋₃alkyl(OH), heterocycle selected from morpholinyl, piperazinyl,piperidinyl and pyrrolidinyl or phenyl, each alkyl, alkenyl, heterocycleand phenyl are optionally substituted by one to three hydroxy, C₁₋₃alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl amino, amino or C₁₋₅alkoxycarbonyl; wherein each R₆ is further optionally covalentlyattached to groups chosen from: hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆cycloalkylC₀₋₂alkyl, benzyloxy, phenylC₀₋₄ alkyl, piperazinylC₀₋₄ alkyl,piperidinyl C₀₋₄alkyl, pyrrolidinylC₀₋₄ alkyl, morpholinylC₀₋₄ alkyl,triazolyl C₀₋₄alkyl, imidazolyl C₀₋₄alkyl and pyridinyl C₀₋₄alkyl, eachabove-listed heterocycle, heteroaryl and phenyl group is optionallysubstituted by one to three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅alkoxycarbonyl, amino, NR₇R₈—C(O)— or C₁₋₄ acyl; each R₇ and R₈ areindependently hydrogen, phenylC₀₋₂alkyl optionally subtituted byhalogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino, or R₇ and R₈ are C₁₋₅branched or unbranched alkyl optionally substituted by C₁₋₄ alkoxy,hydroxy or mono or diC₁₋₃ alkyl amino; R^(b) is chosen from hydrogen,C1-5 alkyl, C3-7 cycloalkylC0-2 alkyl, aryl, C1-5 alkoxy, amino, C1-5alkylamino, C1-3 dialkylamino, C1-3 acyl, C1-5 alkoxycarbonyl, C1-3acyloxy, C1-3 acylamino, C1-3 sulphonylamino, hydroxy, halogen,trifluoromethyl, nitro, nitrile; or R^(b) is chosen from pyrrolidinyl,pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,thiomorpholinyl sulfone, piperidinyl, piperazinyl, piperidinonyl,tetrahydropyrimidonyl, aziridinyl, isoxazolyl, oxazolyl, thiazolyl,thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl and pyridazinyl.
 5. The compound according toclaim 4 and wherein: Ar¹ is formula (A) or (B)

 wherein: when Ar¹ is formula (A) then: R¹ is NH₂,J-N(R^(a))—(CH₂)_(m)—, NH₂C(O)—, J-N(R^(a))—C(O)—, J-S(O)₂—N(R^(a))—,J-N(R^(a))—S(O)₂— or heterocycle-(CH₂)₁₋₂— wherein the heterocycle ischosen from pyrrolidinyl, morpholinyl and piperazinyl each optionallysubstituted by C1-4 alkyl, and J is C₁₋₅ alkyl optionally substituted byR^(b); or when Ar¹ is formula (B) then: R¹ is hydrogen or halogen; R₂ isindependently chosen from C1-5 alkyl, C3-6 cycloalkyl optionallysubstituted by C1-3 alkyl and C1-5 alkoxy, each being optionallypartially or fully halogenated; R⁶ is chosen from a bond, —O—,—O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branched or unbranched, C₂₋₅alkenyl, C₁₋₃ alkyl(OH), heterocycle selected from morpholinyl,piperazinyl, piperidinyl and pyrrolidinyl or phenyl, each alkyl,alkenyl, heterocycle and phenyl are optionally substituted by one tothree hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl amino,amino or C₁₋₅ alkoxycarbonyl; wherein each R₆ is further optionallycovalently attached to groups chosen from: hydrogen, —NR₇R₈, C₁₋₃ alkyl,C₃₋₆ cycloalkylC₀₋₂alkyl, benzyloxy, phenylC₀₋₄ alkyl, piperazinyl,piperazinylC₁₋₂ alkyl, piperidinyl, piperidinyl C₁₋₂alkyl, pyrrolidinyl,pyrrolidinyl C₁₋₂ alkyl, morpholinyl, morpholinylC₁₋₂ alkyl, triazolyl,triazolyl C₁₋₂alkyl, imidazolyl, imidazolyl C₁₋₂alkyl, pyridinyl andpyridinyl C₁₋₂alkyl, each above-listed heterocycle, heteroaryl andphenyl group is optionally substituted by one to three hydroxy, oxo,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, amino, NR₇R₈—C(O)— or C₁₋₄acyl.
 6. The compound according to claim 5 and wherein: Ar¹ is formula(A) or (B)

 and R² is chosen from

 and when Ar¹ is formula (A) then: when R¹ is J-S(O)₂—N(R^(a))— orJ-N(R^(a))—S(O)₂— then J is C₁₋₃ alkyl; and when R¹ is NH₂,J-N(R^(a))—(CH₂)_(m)—, NH₂C(O)—, J-N(R^(a))—C(O)—, orheterocycle-(CH₂)₁₋₂— wherein the heterocycle is chosen frompyrrolidinyl, morpholinyl, piperazinyl or C1-4alkylpiperazinyl, then Jis C1-3 alkyl optionally substituted by R^(b).
 7. The compound accordingto claim 6 and wherein: R^(b) is chosen from hydrogen, C1-5 alkyl, C3-6cycloalkylC0-2 alkyl, phenyl, C1-5 alkoxy, amino, C1-5 alkylamino, C1-3dialkylamino, C1-3 acyl, C1-5 alkoxycarbonyl, C1-3 acyloxy, C1-3acylamino, hydroxy, halogen; or R^(b) is chosen from morpholinyl,thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone,piperidinyl, piperidinonyl, pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl.
 8. The compound according to claim 7 and wherein: R^(b) ischosen from amino, C1-5 alkylamino, C1-3 dialkylamino; or R^(b) ischosen morpholinyl, piperidinyl and pyridinyl.
 9. The compound accordingto claim 6 and wherein: Ar¹ is formula (A).
 10. The compound accordingto claim 6 and wherein: Ar¹ is formula (B).
 11. The compound accordingto claim 6 and wherein: Ar¹ is


12. A compound chosen from:1-Methyl-7-(pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl- 3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-2-methoxy-phenyl)-amide7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Cyclopropylamino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(4-Methoxy-benzylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-phenyl)-amide1-Methyl-7-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(3-Dimethylamino-propylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(3-Dimethylamino-2,2-dimethyl-propylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide7-(2-Dimethylamino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(6-methyl-2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(2-pyrrolidin-1-yl-ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(piperidin-4-ylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide4-{4-[2-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-yloxy]-pyrimidin-2-ylamino}-piperidine-1-carboxylicacid tert-butyl ester7-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-pyrimidin-4-yloxy}-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[6-methyl-2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(2-Dimethylamino-ethoxy)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(2-Dimethylamino-ethoxy)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-phenyl)-amide1-Methyl-7-[2-(2-pyrrolidin-1-yl-ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(1-methyl-piperidin-4-yloxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(2-Dimethylamino-ethoxy)-6-methyl-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-methylcarbamoyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid[5-tert-butyl-3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide7-[2-(2-Dimethylamino-ethylcarbamoyl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid[5-tert-butyl-3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid[5-tert-butyl-2-methoxy-3-(2-morpholin-4-yl-ethylcarbamoyl)-phenyl]-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-3-carbamoyl-2-methoxy-phenyl)-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-2-methoxy-3-methylcarbamoyl-phenyl)-amide1-Methyl-7-(2-vinyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(1,2-Dihydroxy-ethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(morpholin-4-ylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-morpholin-4-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-morpholin-4-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Dimethylaminomethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-methylcarbamoyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Benzyloxymethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5- tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-2-methoxy-3-morpholin-4-ylmethyl-phenyl)-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid[5-tert-butyl-2-methoxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-3-dimethylaminomethyl-2-methoxy-phenyl)-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(3- amino-5-tert-butyl-2-methoxy-phenyl)-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-3-dibenzylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-2-methoxy-3-methylsulfamoyl-phenyl)-amide7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-[1,3]dioxolan-2-yl-2-methoxy-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-3-methylaminomethyl-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-2-methoxy-3-pyrrolidin-1-ylmethyl-phenyl)-amide1-Methyl-7-{2-[methyl-(1-methyl-piperidin-4-yl)-amino]-pyrimidin-4-yloxy}-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Hydroxymethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5- tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide and1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid[5-tert-butyl-2-methoxy-3-(2-morpholin-4-yl-ethylamino)-phenyl]-amide1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-piperazin-1-yl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide1-Methyl-7-[2-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Methoxy-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5-tert- butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(4-tert-Butyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-{2-[2-(4-methyl-piperazin-1-yl)-ethyl]-pyrimidin-4-yloxy}-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(2-pyrrolidin-1-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(2-Dimethylamino-ethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide7-{2-[2-(4-tert-Butyl-piperazin-1-yl)-ethyl]-pyrimidin-4-yloxy}-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(4-tert-Butyl-piperazin-1-ylmethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2,6-Dimethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5-tert- butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Ethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl- 3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Amino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5-tert- butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-piperidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-2-methoxy-phenyl)-amide7-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-3-carbamoyl-2-methoxy-phenyl)-amide1-Methyl-7-[2-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2- methoxy-phenyl)-amide1-Methyl-7-[2-(4-methyl-[1,4]diazepan-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-[1,4]Diazepan-1-yl-pyridin-4-yloxy)-1-methyl-1-H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-piperazin-1-yl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-trideuterio-7-(2-piperazin-1-yl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(5- tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-trideuterio-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide7-[2-((S)-3-Dimethylamino-pyrrolidin-1-yl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide7-[2-((S)-3-Dimethylamino-pyrrolidin-1-yl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide1-Methyl-7-[2-(4-methyl-piperazine-1-carbonyl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide and1-Methyl-7-[2-(piperazine-1-carbonyl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

or the pharmaceutically acceptable salts, acids or isomers thereof. 13.A compound chosen from:7-(Pyrimidin-4-yloxy)-benzo[b]thiophene-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(Pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(Pyrimidin-4-yloxy)-benzofuran-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(pyrimidin-4-ylsulfanyl)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(pyrimidin-4-ylamino)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(pyridin-3-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Benzylamino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-{2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(2-Imidazol-1-yl-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(2-[1,2,3]triazol-1-yl-ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(3-Dimethylamino-propylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid[2-methoxy-5-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-phenyl]-amide7-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-pyrimidin-4-yloxy}-1-methyl-1H-indole-2-carboxylic acid(4-chloro-2-methoxy-5-trifluoromethyl-phenyl)-amide7-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(4-chloro-2-methoxy-5-trifluoromethyl-phenyl)-amide7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(2-methoxy-5- trifluoromethoxy-phenyl)-amide7-[2-(4-Dimethylamino-piperidin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(3-Dimethylamino-pyrrolidin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(1-methyl-piperidin-4-ylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(1-Acetyl-piperidin-4-ylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide7-[2-(2-Imidazol-1-yl-ethoxy)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-(2-Imidazol-1-yl-ethoxy)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(4-chloro-2-methoxy-5-trifluoromethyl-phenyl)-amide7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-3-methylcarbamoyl-phenyl)-amide7-(2-Amino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-carbamoyl-2-methoxy-phenyl)-amide7-(2-Amino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid[5-tert-butyl-3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-dimethylaminomethyl-2-methoxy-phenyl)-amide7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-3-pyrrolidin-1-ylmethyl-phenyl)-amide7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-3-morpholin-4-ylmethyl-phenyl)-amide1-Methyl-7-(2-morpholin-4-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(4-chloro-2-methoxy-5-trifluoromethyl-phenyl)-amide7-[2-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Carbamoyl-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-morpholin-4-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(2-methoxy-3-morpholin-4-ylmethyl-5-trifluoromethyl-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(2-methoxy-3-morpholin-4-ylmethyl-5-trifluoromethyl-phenyl)-amide1-Methyl-7-(2-morpholin-4-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(3-methanesulfonylaniino-2-methoxy-5-trifluoromethyl-phenyl)-amide 7-(1′-tert-Butyl-1′,2′,3′,4^(′),5′,6′-hexahydro-[2,4′]bipyridinyl-4-yloxy)-1-methyl-1H- indole-2-carboxylicacid(3-methanesulfonylamino-2-methoxy-5- trifluoromethyl-phenyl)-amide1-Methyl-7-(2-methylaminomethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylic acid(2-methoxy-3-morpholin-4-ylmethyl-5-trifluoromethyl-phenyl)-amide 1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(3-dimethylaminomethyl-2-methoxy-5-trifluoromethyl-phenyl)-amide1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(2-methoxy-3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl)-amide7-(2-Dimethylaminomethyl-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid[2-methoxy-3-(4-methyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-amide7-(2-Dimethylaminomethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide7-(2-Dimethylaminomethyl-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide7-(2-Dimethylaminomethyl-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide1-Methyl-7-[2-(1-methyl-piperidin-4-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-[2-1-Cyclopropyl-piperidin-4-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(3-dimethylaminomethyl-2-methoxy-5-trifluoromethyl-phenyl)-amide and1-Methyl-7-[2-(1-methyl-pyrrolidin-3-ylamino)-pyridin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

or the pharmaceutically acceptable salts, acids or isomers thereof. 14.A pharmaceutical composition containing a pharmaceutically effectiveamount of a compound according to claim 1 and one or morepharmaceutically acceptable carriers and/or adjuvants.
 15. A method oftreating an oncological disease comprising administering to a patient apharmaceutically effective amount of a compound according to claim 1.16. A method of treating a disease or condition chosen fromosteoarthritis, atherosclerosis, contact dermatitis, bone resorptiondiseases, reperfusion injury, asthma, multiple sclerosis, Guillain-Barresyndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versushost disease, systemic lupus erythematosus, insulin-dependent diabetesmellitus, rheumatoid arthritis, toxic shock syndrome, Alzheimer'sdisease, diabetes, inflammatory bowel diseases, acute and chronic pain,stroke, myocardial infarction alone or following thrombolytic therapy,thermal injury, adult respiratory distress syndrome (ARDS), multipleorgan injury secondary to trauma, acute glomerulonephritis, dermatoseswith acute inflammatory components, acute purulent meningitis, syndromesassociated with hemodialysis, leukopherisis, granulocyte transfusionassociated syndromes, necrotizing entrerocolitis, restenosis followingpercutaneous transluminal coronary angioplasty, traumatic arthritis,sepsis, chronic obstructive pulmonary disease and congestive heartfailure, said method comprising administering to a patient apharmaceutically effective amount of a compound according to claim 1.17. A method of treating a disease or condition requiring anticoagulantor fibrinolytic therapy, said method comprising administering to apatient a pharmaceutically effective amount of a compound according toclaim
 1. 18. A process of making a compound of the formula (I):

Ar₁, X, Y, Q, W, R³, R⁴, R⁵, R⁶and R^(y) are defined in claim 1; saidprocess comprising coupling under suitable conditions an amine bearingAr¹ carboxylic acid of the formula (III), where P is a protecting group,removing the protecting group P to provide an intermediate of formula(V) under suitable conditions; coupling under suitable conditions theintermediate (V) with a halo heterocycle VI (Z=halogen) bearing R⁶ inthe presence of a suitable base to provide a compound of the formula(I):